Epigenetic control of adamantinomatous craniopharyngiomas.

INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 ACP patients (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multi-dimensional scaling. Statistical associations between clusters and clinical features were achieved using Fisher's test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = 0.0006), hypomethylated in CpG Island (CGI), non-CGI sites, and globally (P < 0.001), and associated with greater tumor size (24.1 vs 9.5cm3, P = 0.04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell-adhesion, cytoskeleton organization, and cytokine binding, and also cell-type specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of ACP patients were consistently revealed by unsupervised machine learning methods, being one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.

Integrating Methylome and Transcriptome Signatures Expands the Molecular Classification of the Pituitary Tumors.

OBJECTIVE: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. METHODS: In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. RESULTS: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). CONCLUSION: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.

Telomere length and Wnt/ß-catenin pathway in adamantinomatous craniopharyngiomas.

Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.

Corpus callosum size, hypnotic susceptibility and empathy in women with alleged mediumship: a controlled study.

AIM: Evidence indicates that highly hypnotizable subjects may have larger area of the rostrum of the corpus callosum (CC). Mediumship can be defined as the alleged ability to communicate regularly with deceased personalities, and self-hypnosis is postulated as an underlying mechanism for this ability. Therefore, we aimed to investigate the CC area, hypnotic susceptibility, self-reported dissociation, and empathy in alleged mediums in comparison with healthy, non-medium controls. METHODS: The study sample consisted of 16 Spiritist mediums (medium group (MG)) and 16 non-medium controls. Magnetic resonance imaging scans were performed to measure the CC areas (total and subdivisions). The Harvard Group Scale of Hypnotic Susceptibility was used to assess hypnotizability, and self-reported measures were used to investigate anomalous experiences, mental health using the Self-Reporting Questionnaire-SRQ, dissociative experiences using the Dissociative Experiences Scale, and empathy using the Interpersonal Reactivity Index. RESULTS: No between-group differences were found in the total or subdivided CC areas or in hypnotizability, with both groups showing intermediate levels. The rostrum of the CC area and hypnotizability were not correlated. The MG presented with significantly more anomalous experiences, but the two groups had similar scores for dissociation, empathy, and mental health. CONCLUSION: The normal CC areas found in the MG are in contrast with the abnormal results typically observed in subjects with psychotic and dissociative disorders. Although hypnotizability was not different between groups, further studies are needed to replicate these findings in other samples.

"Seat of the soul"? The structure and function of the pineal gland in women with alleged spirit possession-Results of two experimental studies.

BACKGROUND: Cultural traditions attribute to pineal gland an important role for spiritual experiences. Mediumship and spirit possession are cultural phenomena found worldwide which have been described as having dissociative and psychotic-like characteristics, but with nonpathological aspects. A sympathetic activation pattern in response to spirit possession has been reported in some studies, but empirical data on pineal gland is scarce in this context. METHODS: We aimed to investigate pineal gland and pituitary volumes, as well as urinary 6-sulfatoxymelatonin levels in 16 alleged mediums (Medium Group-MG) compared with 16 healthy nonmedium controls (Control Group) (Experiment 1). Furthermore, we aimed to evaluate urinary 6-sulfatoxymelatonin and stress reactivity in GM (n = 10) under different physiological conditions (Experiment 2). RESULTS: In Experiment 1, MG presented higher scores of anomalous experiences, but there were no between-group differences regarding mental health or subjective sleep quality. Similar pineal gland and pituitary volumes were observed between groups. There were no between-group differences in urinary 6-sulfatoxymelatonin collected under equivalent baseline conditions. In Experiment 2, the rise of anxiety and heart rate in response to mediumistic experience was intermediate between a nonstressful control task (reading) and a stressful control task (Trier Social Stress Test-TSST). No significant differences were observed in 6-sulfatoxymelatonin urinary levels between the three conditions. The pattern of stress reactivity during the TSST was normal, but with an attenuated salivary cortisol response. CONCLUSION: The normal neuroimaging and stress reactivity findings in MG contrast with the abnormal results usually observed in subjects with psychotic and dissociative disorders.

Refluxo gastroesofágico: estudo comparativo da receptividade e sensibilidade entre seriografia e ultrassonografia / Gastroesophageal reflux: a comparative study of receptiveness and sensitivity of upper gastrointestinal series and ultrasonography

OBJETIVO: Estudo comparativo da receptividade (colaboração) e sensibilidade da seriografia do esôfago, estômago e duodeno em relação à ultrassonografia do esôfago intra-abdominal em pacientes com suspeita de refluxo gastroesofágico. MATERIAIS E MÉTODOS: Foram incluídos no estudo 42 pacientes pediátricos (26 masculinos, com idade média de 33,64 ± 34,33 meses, e 16 femininos, com idade média de 31,02 ± 35,56 meses) com suspeita de refluxo gastroesofágico, os quais foram submetidos, inicialmente, a seriografia do esôfago, estômago e duodeno, e posteriormente, a ultrassonografia do esôfago intra-abdominal. RESUL-TADOS: A análise estatística comparativa entre os sexos e as idades sugere não haver evidência de associação com a colaboração, tanto para a seriografia do esôfago, estômago e duodeno como para a ultrassonografia do esôfago intra-abdominal. Entretanto, na classificação quanto ao tipo de colaboração, a técnica de seriografia do esôfago, estômago e duodeno apresentou menos de 50 por cento de colaboração, enquanto 80,49 por cento dos pacientes colaboraram com a ultrassonografia do esôfago intra-abdominal. Quanto à sensibilidade do diagnóstico de refluxo gastroesofágico, a técnica de ultrassonografia do esôfago intra-abdominal (85,7 por cento) foi significativamente superior à de seriografia do esôfago, estômago e duodeno (47,6 por cento). CONCLUSÃO: O presente estudo sugere que se proceda a ultrassonografia do esôfago intra-abdominal, mesmo na ausência de refluxo gastroesofágico na seriografia do esôfago, estômago e duodeno.

OBJECTIVE: Comparative study of receptiveness (cooperation) and sensitivity of upper gastrointestinal series and intraabdominal esophagus ultrasonography in patients with suspicion of gastroesophageal reflux. MATERIALS AND METHODS: The present study included 42 pediatric patients (26 male, with mean age of 33.64 ± 34.33 months, and 16 female, with mean age of 31.02 ± 35.56 months) with suspicion of gastroesophageal reflux, who were initially submitted to upper gastrointestinal series and subsequently to intraabdominal esophagus ultrasonography. RESULTS: The statistical comparative analysis covering sexes and ages suggests no evidence of association with cooperation, both for the upper gastrointestinal series and the intraabdominal esophagus ultrasonography. However, in the classification of the patients' cooperation, the technique of upper gastrointestinal series presented less than 50 percent of cooperation, while 80.49 percent of patients cooperated in the intraabdominal esophagus ultrasonography examinations. As regards the methods sensitivity for the diagnosis of gastroesophageal reflux, the technique of intraabdominal esophagus ultrasonography was significantly superior (85.7 percent) to the upper gastrointestinal series (47.6 percent). CONCLUSION: The present study suggests that an intraabdominal esophagus ultrasonography should be performed even if gastroesophageal reflux even if it is not detected at the upper gastrointestinal series.