FGFR Alterations in Thyroid Carcinoma: A Novel Class of Primary Drivers with Significant Therapeutic Implications and Secondary Molecular Events Potentially Mediating Resistance in Thyroid Malignancy.

Background Diagnostic classification of thyroid malignancy is primarily accomplished through examination of histomorphological features and may be substantiated and clarified by molecular data. Individual molecular drivers show relatively robust and specific associations with histological subtypes of thyroid malignancy, including BRAF sequence variants and kinase gene fusions in papillary thyroid carcinoma, predominantly RAS variants in follicular-patterned neoplasia, and additional "late" mutations affecting TERT promoter, TP53, and the PI3K/AKT/PTEN pathway in high-grade malignancies. Given the oncogenic role of FGFR, particularly FGFR1-3, the goal of this study was to explore the role of FGFR in thyroid carcinoma biology. Methods We completed a multi-center retrospective observational study for thyroid carcinomas with pathogenic alterations in the FGFR gene family. We performed this study by querying the molecular data accumulated for thyroid carcinomas from each center. Results Overall, 5,030 sequenced thyroid malignancies were reviewed, yielding 17 tumors with FGFR alterations, including 11 where FGFR was the primary molecular driver and 6 where FGFR was a secondary pathogenic alteration, with a subset for which there was available clinical follow-up data. Of the 11 carcinomas with an FGFR driver, 9 were gene fusions involving FGFR2::VCL (4 tumors), TG::FGFR1 (3 tumors), FGFR2::CIT, and FGFR2::SHTN1, and the remaining 2 were driven by FGFR1 amplification. In the 6 tumors where a canonical driver of thyroid neoplasia was present (5 cases) or no clear primary driver was detected (1 case), sequencing detected secondary FGFR2 p.W290C, p.Y375C, and p.N549K, as well as FGFR1 p.N546K in the respective tyrosine kinase domains, some at subclonal variant allele frequencies. Conclusions This study presents the first description of a collection of thyroid carcinomas grouped by primary driver alterations in FGFR, as well as a cohort of thyroid tumors with secondary alterations that potentially lead to tumor progression or resistance to targeted therapy. Given the availability of small molecular inhibitors targeting oncogenic FGFR, this study emphasizes the significant implications for patients from identification of FGFR alterations as they are currently under-recognized in the literature and, most importantly, have potential novel treatment options.

Acute Promyelocytic Leukemia With Torque Teno Mini Virus::RARA Fusion: An Approach to Screening and Diagnosis.

Acute promyelocytic leukemia (APL) with variant RARA translocation is linked to over 15 partner genes. Recent publications encompassing 6 cases have expanded the spectrum of RARA partners to torque teno mini virus (TTMV). This entity is likely underrecognized due to the lack of clinician and pathologist familiarity, inability to detect the fusion using routine testing modalities, and informatic challenges in its recognition within next-generation sequencing (NGS) data. We describe a clinicopathologic approach and provide the necessary tools to screen and diagnose APL with TTMV::RARA using existing clinical DNA- or RNA-based NGS assays, which led to the identification of 4 cases, all without other known cytogenetic/molecular drivers. One was identified prospectively and 3 retrospectively, including 2 from custom automated screening of multiple data sets (50,257 cases of hematopoietic malignancy, including 4809 acute myeloid leukemia/myeloid sarcoma/APL cases). Two cases presented as myeloid sarcoma, including 1 with multiple relapses after acute myeloid leukemia-type chemotherapy and hematopoietic stem cell transplant. Two cases presented as leukemia, had a poor response to induction chemotherapy, but achieved remission upon reinduction (including all-trans retinoic acid in 1 case) and subsequent hematopoietic stem cell transplant. Neoplastic cells demonstrated features of APL including frequent azurophilic granules and dim/absent CD34 and HLA-DR expression. RARA rearrangement was not detected by karyotype or fluorescent in situ hybridization. Custom analysis of NGS fusion panel data identified TTMV::RARA rearrangements and, in the prospectively identified case, facilitated monitoring in sequential bone marrow samples. APL with TTMV::RARA is a rare leukemia with a high rate of treatment failure in described cases. The diagnosis should be considered in leukemias with features of APL that lack detectable RARA fusions and other drivers, and may be confirmed by appropriate NGS tests with custom informatics. Incorporation of all-trans retinoic acid may have a role in treatment but requires accurate recognition of the fusion for appropriate classification as APL.

How theory of mind leads to positive first impressions.

A common conjecture is that social success relies on "theory of mind"-the everyday skill of imputing mental states to others. We test the hypothesis that individuals with stronger theory of mind skills and motivation garner more positive first impressions because of how they interact with others. Participants included 334 young adults who were paired with a peer for a first-time meeting. Dyads completed a cooperative Lego-building task, which was videotaped and later coded for behavioral manifestations of theory of mind by independent raters. Theory of mind accuracy and motivation were assessed with validated laboratory tasks and a self-report questionnaire, respectively. First impressions were assessed based on partner's ratings of participant likeability, enjoyment of the interaction, and changes in positive affect. Results of actor-partner interdependence mediation models revealed that the associations between theory of mind and first impressions are indirect and mediated through behaviors. Specifically, participants with stronger theory of mind demonstrated greater cognitive sensitivity and pragmatic conversational skills. However, only cognitive sensitivity subsequently predicted more favorable first impressions. This research shows that social-cognitive skills can affect others' social impressions through their behavioral manifestations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

ERP responses to sexual cues among young women attracted to men.

Previous event-related potential (ERP) studies reported larger N170, P3, and late positive potential (LPP) amplitudes to sexual than nonsexual stimuli. These ERPs may not be specifically sensitive to processing sexual cues, however, because the sexual stimuli included information beyond sexual cues (e.g., faces, bodies, social interaction) to a greater extent than comparison stimuli. We investigated ERPs to stimuli that focused on sexual and nonsexual body regions, in different states of readiness for activity, to elucidate neural responses involved in processing sexual cues. Forty cisgender, primarily white, undergraduate women who were attracted to men (Mage  = 18.6, SD = 0.9) viewed images that varied by male body part (penis, arm) and activity state (rest, poised for activity). Participants viewed 40 images per category (flaccid penises, erect penises, outstretched arms, bent arms). Electroencephalography (EEG) was recorded using a 128-channel net, time-locked to the onset of each image. Using a whole-head cluster-mass approach, we found that the P3 was sensitive to sexual readiness-P3 amplitudes were larger to erect than flaccid penises, but not to bent than outstretched arms. The N170 and LPP components did not show evidence of similarly specific responses to sexual readiness, revealing potential dissociation of different neural processes commonly elicited in response to more complex sexual stimuli. An additional novel finding was that an anterior N270-400 was sensitive to sexual readiness. Findings clarify the brain's rapid responses to sexual stimuli, setting the stage for future research aimed at better understanding the neurocognitive processes that contribute to the coordination of sexual arousal.

Identification of the NRF2 transcriptional network as a therapeutic target for trigeminal neuropathic pain.

Trigeminal neuralgia, historically dubbed the "suicide disease," is an exceedingly painful neurologic condition characterized by sudden episodes of intense facial pain. Unfortunately, the only U.S. Food and Drug Administration (FDA)-approved medication for trigeminal neuralgia carries substantial side effects, with many patients requiring surgery. Here, we identify the NRF2 transcriptional network as a potential therapeutic target. We report that cerebrospinal fluid from patients with trigeminal neuralgia accumulates reactive oxygen species, several of which directly activate the pain-transducing channel TRPA1. Similar to our patient cohort, a mouse model of trigeminal neuropathic pain also exhibits notable oxidative stress. We discover that stimulating the NRF2 antioxidant transcriptional network is as analgesic as inhibiting TRPA1, in part by reversing the underlying oxidative stress. Using a transcriptome-guided drug discovery strategy, we identify two NRF2 network modulators as potential treatments. One of these candidates, exemestane, is already FDA-approved and may thus be a promising alternative treatment for trigeminal neuropathic pain.

Event-related potential studies of cross-situational word learning in four-year-old children.

Young children learn word-referent links in cross-situational learning paradigms despite uncertainty as to a given word's correct referent on individual exposures. However, the semantic status of these word-referent links is unknown. Here, we used a novel event-related potential (ERP) testing approach to investigate whether children showed electrophysiological signatures of semantic representations following a typical cross-situational learning paradigm. In Study 1, 20 4-year-old children (mean age: 51.35 months) learned eight new word-object pairs in a cross-situational learning task which included familiar object labeling before training. Then, they completed an ERP task which involved seeing pictures of the novel objects and then hearing words that were either congruent or incongruent with the word-referent association that was trained. Results showed a robust N400 ERP effect, thereby providing evidence for having acquired a semantic representation during the cross-situational learning paradigm. Children also showed good performance on a comprehension test approximately 20 min after training. In a second study, a different sample of 20 4-year-old children (mean age: 52 months) completed the same cross-situational task but without the initial familiar word pretraining. Here, we did not see the N400 effect we saw in Study 1, but children still showed good performance on the delayed comprehension test. We conclude that rapid semantic encoding can occur during cross-situational learning, but that pretraining on the structure of the paradigm may be critical for facilitating that encoding. We speculate on the mechanisms by which pretraining might have effects and discuss the implications of these findings for early word learning.

Theory of mind in dysphoric and non--dysphoric adults: An ERP study of true-- and false--belief reasoning.

Theory of mind (ToM) - the understanding that others' behaviors are connected with internal mental states - is an important part of everyday social cognition. There is increasing behavioral evidence that ToM reasoning can be affected by mood. To gain insight into the ways sad mood may affect the underlying mechanisms of ToM reasoning, we recorded event-related brain potentials (ERPs) as dysphoric (N = 16) and non-dysphoric (N = 24) participants reasoned about a protagonist's true or false beliefs about an object's location. Results showed significant group effects on early components of the ERP - individuals in the dysphoric group showed greater amplitudes for the anterior N1 and N2/P2 components relative to those in the non-dysphoric group. Later in the ERP, non-dysphoric individuals showed evidence of neurocognitive dissociations between true and false belief. Dysphoric individuals, however, did not show evidence for these later dissociations. This evidence suggests that dysphoria may be associated with effortful reasoning about other's mental states, even when that effort is not necessary (i.e., when reasoning about true beliefs). We discuss the implications of these findings for understanding how mood affects ToM reasoning and for how especially deliberative ToM processing in dysphoria may lead to social difficulties.

Multidimensional Reasoning Can Promote 3-Year-Old Children's Performance on the Dimensional Change Card Sort Task.

An important aspect of executive functioning is the ability to flexibly switch between behavioral rules. This study explored how considering the multidimensionality of objects affects behavioral rule switching in 3-year-old children. In Study 1 (N = 40), children who participated in a brief game separating and aggregating an object's dimensions (i.e., color and shape) showed improved performance on the Dimensional Change Card Sort (DCCS), a measure of behavioral rule switching, relative to controls. In Study 2 (N = 80) DCCS performance improved even when the initial practice involved a different dimension (pattern and shape). Thus, practice thinking about multidimensionality can affect 3-year-olds' DCCS performance and therefore may play an important role in the development of flexible thinking.

Inhibitory Control and Preschoolers' Use of Irregular Past Tense Verbs.

We investigated whether children's inhibitory control (IC) is associated with their ability to produce irregular past tense verb forms as well as learn from corrective feedback following overregularization errors. Forty-eight 3;6 to 4;5 year old children were tested on the irregular past tense and provided with adult corrective input via models of correct use or recasts of errors following ungrammatical responses. IC was assessed with a three-item battery of tasks that required suppressing a prepotent response in favor of a non-canonical one. Results showed that IC was associated with children's initial production of irregular forms, but not associated with their post-feedback production. Findings are discussed in terms of current theories of past tense use and acquisition.

Valence in the Reading the Mind in the Eyes task.

The Reading the Mind in the Eyes task (RMET; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001) is commonly used to assess theory of mind abilities in adults. In the task, participants pair one of four mental state descriptors with a picture of the eye region of a face. The items have varying emotional valence, and nearly 100 studies have examined whether performance on this task varies with item valence. However, efforts to address this question have been hampered by cross-study inconsistencies in how item valence is assessed. Thus, the goal of this study was to establish reference ratings for the valence of RMET items. In Study 1, we recorded valence ratings for each RMET item with a large sample of raters (n = 164). We illustrated how valence categories are essentially arbitrary and largely influenced by sample size. In addition, valence ratings were continuously distributed, further questioning the validity of imposing categorical distinctions. In Study 2, we used an archival dataset to demonstrate how the different categorization schemes resulted in conflicting conclusions about the association between item valence and RMET performance. However, when we examined the association between item valence and performance in a continuous manner, a clear U-shaped pattern emerged: Items that had more extreme valence ratings (negative or positive) were associated with better performance than items with more neutral ratings. We conclude that using the item valence ratings we report, and treating item valence as a continuous rather than categorical predictor, will help bring consistency to the study of the association between item valence and performance in the RMET. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

A genome-wide view of the de-differentiation of central nervous system endothelial cells in culture.

Vascular endothelial cells (ECs) derived from the central nervous system (CNS) variably lose their unique barrier properties during in vitro culture, hindering the development of robust assays for blood-brain barrier (BBB) function, including drug permeability and extrusion assays. In previous work (Sabbagh et al., 2018) we characterized transcriptional and accessible chromatin landscapes of acutely isolated mouse CNS ECs. In this report, we compare transcriptional and accessible chromatin landscapes of acutely isolated mouse CNS ECs versus mouse CNS ECs in short-term in vitro culture. We observe that standard culture conditions are associated with a rapid and selective loss of BBB transcripts and chromatin features, as well as a greatly reduced level of beta-catenin signaling. Interestingly, forced expression of a stabilized derivative of beta-catenin, which in vivo leads to a partial conversion of non-BBB CNS ECs to a BBB-like state, has little or no effect on gene expression or chromatin accessibility in vitro.

Continuity in the neural system supporting children's theory of mind development: Longitudinal links between task-independent EEG and task-dependent fMRI.

Children's explicit theory of mind (ToM) understandings change over early childhood. We examined whether there is longitudinal stability in the neurobiological bases of ToM across this time period. A previous study found that source-localized resting EEG alpha attributable to the dorsal medial prefrontal cortex (DMPFC) and right temporoparietal junction (RTPJ) was associated with children's performance on a battery of theory of mind tasks. Here, we investigated a small subset of children (N = 12) in that original study as a preliminary investigation of whether behavioral measures of ToM performance, and/or EEG localized to the DMPFC or RTPJ predicted ToM-specific fMRI responses 3.5 years later. Results showed that preschoolers' behavioral ToM-performance positively predicted later ToM-specific fMRI responses in the DMPFC. Preschoolers' resting EEG attributable to the DMPFC also predicted later ToM-specific fMRI responses in the DMPFC. Given the small sample, results represent a first exploration and require replication. Intriguingly, they suggest that early maturation of the area of the DMPFC related to ToM reasoning is positively linked with its specific recruitment for ToM reasoning later in development, affording implications for characterizing conceptual ToM development, and its underlying neural supports.

Beta-catenin signaling regulates barrier-specific gene expression in circumventricular organ and ocular vasculatures.

The brain, spinal cord, and retina are supplied by capillaries that do not permit free diffusion of molecules between serum and parenchyma, a property that defines the blood-brain and blood-retina barriers. Exceptions to this pattern are found in circumventricular organs (CVOs), small midline brain structures that are supplied by high permeability capillaries. In the eye and brain, high permeability capillaries are also present in the choriocapillaris, which supplies the retinal pigment epithelium and photoreceptors, and the ciliary body and choroid plexus, the sources of aqueous humor and cerebrospinal fluid, respectively. We show here that (1) endothelial cells in these high permeability vascular systems have very low beta-catenin signaling compared to barrier-competent endothelial cells, and (2) elevating beta-catenin signaling leads to a partial conversion of permeable endothelial cells to a barrier-type state. In one CVO, the area postrema, high permeability is maintained, in part, by local production of Wnt inhibitory factor-1.

Activation of Mast-Cell-Expressed Mas-Related G-Protein-Coupled Receptors Drives Non-histaminergic Itch.

Classical itch studies have focused on immunoglobulin E (IgE)-mediated mast cell activation and histamine release. Recently, members of the Mas-related G-protein-coupled receptor (Mrgpr) family have been identified as mast cell receptors, but their role in itch is unclear. Here, we report that mast cell activation via Mrgprb2 evoked non-histaminergic itch in mice independently of the IgE-Fc epsilon RI (FcεRI)-histamine axis. Compared with IgE-FcεRI stimulation, Mrgprb2 activation of mast cells was distinct in both released substances (histamine, serotonin, and tryptase) and the pattern of activated itch-sensory neurons. Mrgprb2 deficiency decreased itch in multiple preclinical models of allergic contact dermatitis (ACD), a pruritic inflammatory skin disorder, and both mast cell number and PAMP1-20 concentrations (agonist of the human Mrgprb2 homolog, MRGPRX2) were increased in human ACD skin. These findings suggest that this pathway may represent a therapeutic target for treating ACD and mast-cell-associated itch disorders in which antihistamines are ineffective.

Affinity capture of polyribosomes followed by RNAseq (ACAPseq), a discovery platform for protein-protein interactions.

Defining protein-protein interactions (PPIs) is central to the biological sciences. Here, we present a novel platform - Affinity Capture of Polyribosomes followed by RNA sequencing (ACAPseq) - for identifying PPIs. ACAPseq harnesses the power of massively parallel RNA sequencing (RNAseq) to quantify the enrichment of polyribosomes based on the affinity of their associated nascent polypeptides for an immobilized protein 'bait'. This method was developed and tested using neonatal mouse brain polyribosomes and a variety of extracellular domains as baits. Of 92 baits tested, 25 identified one or more binding partners that appear to be biologically relevant; additional candidate partners remain to be validated. ACAPseq can detect binding to targets that are present at less than 1 part in 100,000 in the starting polyribosome preparation. One of the observed PPIs was analyzed in detail, revealing the mode of homophilic binding for Protocadherin-9 (PCDH9), a non-clustered Protocadherin family member.

Transcriptional and epigenomic landscapes of CNS and non-CNS vascular endothelial cells.

Vascular endothelial cell (EC) function depends on appropriate organ-specific molecular and cellular specializations. To explore genomic mechanisms that control this specialization, we have analyzed and compared the transcriptome, accessible chromatin, and DNA methylome landscapes from mouse brain, liver, lung, and kidney ECs. Analysis of transcription factor (TF) gene expression and TF motifs at candidate cis-regulatory elements reveals both shared and organ-specific EC regulatory networks. In the embryo, only those ECs that are adjacent to or within the central nervous system (CNS) exhibit canonical Wnt signaling, which correlates precisely with blood-brain barrier (BBB) differentiation and Zic3 expression. In the early postnatal brain, single-cell RNA-seq of purified ECs reveals (1) close relationships between veins and mitotic cells and between arteries and tip cells, (2) a division of capillary ECs into vein-like and artery-like classes, and (3) new endothelial subtype markers, including new validated tip cell markers.

Childhood emotional abuse, physical abuse, and neglect are associated with theory of mind decoding accuracy in young adults with depression.

The current study is the first to examine the relation of childhood abuse and neglect history to theory of mind decoding accuracy as moderated by depression. Fifty-five young adults with current or lifetime unipolar depression diagnosis and 70 never-depressed young adults completed the 'Reading the Mind in the Eyes task,' (RMET). Childhood emotional abuse, physical abuse, and neglect were assessed with a gold-standard contextual interview with standardized, independent ratings. Poorer RMET accuracy was associated with a history of emotional abuse in the depressed group and a history of physical abuse in the non-depressed group. In contrast, across both groups, those with a history of neglect showed significantly enhanced theory of mind decoding accuracy compared to those without. Further, differential accuracy across positive, negative, and neutral valenced stimuli in the RMET was observed in each model. These findings indicate that distinct theory of mind performance results from early experiences of threat versus deprivation, and suggest that early intervention may be most successful in preventing negative interpersonal outcomes of maltreatment by focusing on remediating theory of mind deficits resulting from abuse, and tempering heightened sensitivity in those exposed to neglect.

Children remember words from ignorant speakers but do not attach meaning: evidence from event-related potentials.

Although we know much about the conditions under which children demonstrate selective social learning, we have a limited understanding of the cognitive mechanisms by which children's selectivity manifests. Here, we report findings from a brain electrophysiological (ERP) study designed to determine the extent to which words presented by ignorant speakers were later both familiar to children and associated with semantic meaning. Forty-eight children (mean age = 6.5 years) first experienced novel word training from either a knowledgeable or an ignorant speaker. Children's ERPs were subsequently recorded as they heard a recording of the speaker using the novel word, followed by a picture of either the object the word was paired with during training (congruent) or a distractor object that was also present during training (incongruent). Children trained by a knowledgeable speaker showed both N200 and N400 effects to the incongruent word-referent pairings, thereby suggesting that the novel words were both familiar and bore a semantic association. In contrast, children trained by an ignorant speaker demonstrated only the N200 effect, thereby suggesting that the word-referent links were familiar, but not associated with semantic meaning. These findings provide evidence that selective word learning involves the disruption of processes specifically associated with semantic consolidation of word learning events.

Conceptual constraints and mechanisms in children's selective learning.

Although we can support Heyes' call for more research on mechanisms, we disagree that the problem has been ignored as Heyes suggests. We also doubt that basic learning mechanisms are alone sufficient to account for the broad range of findings in the selective social learning literature. Although phylogenetically shared learning mechanisms must support selective social learning, we believe that they must also be guided by top-down conceptual considerations that may be special to humans. Research to date has been focused on establishing the boundary conditions on selective social learning, with the goal of making generalizations that will constrain theorizing about the character of that special knowledge. This is critical to our understanding of both why and how selective social learning manifests in children.

Serotonin and Dopamine Gene Variation and Theory of Mind Decoding Accuracy in Major Depression: A Preliminary Investigation.

Theory of mind-the ability to decode and reason about others' mental states-is a universal human skill and forms the basis of social cognition. Theory of mind accuracy is impaired in clinical conditions evidencing social impairment, including major depressive disorder. The current study is a preliminary investigation of the association of polymorphisms of the serotonin transporter (SLC6A4), dopamine transporter (DAT1), dopamine receptor D4 (DRD4), and catechol-O-methyl transferase (COMT) genes with theory of mind decoding in a sample of adults with major depression. Ninety-six young adults (38 depressed, 58 non-depressed) completed the 'Reading the Mind in the Eyes task' and a non-mentalistic control task. Genetic associations were only found for the depressed group. Specifically, superior accuracy in decoding mental states of a positive valence was seen in those homozygous for the long allele of the serotonin transporter gene, 9-allele carriers of DAT1, and long-allele carriers of DRD4. In contrast, superior accuracy in decoding mental states of a negative valence was seen in short-allele carriers of the serotonin transporter gene and 10/10 homozygotes of DAT1. Results are discussed in terms of their implications for integrating social cognitive and neurobiological models of etiology in major depression.