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Objective: Borderline personality disorder (BPD) and eating disorders (EDs) both cause significant distress and co-occur at rates higher than expected, signifying potential overlapping regulatory mechanisms between both disorders. More specifically, both disorders involve emotion regulation deficits, suggesting they may share specific maladaptive regulatory components. The present study sought to examine the predictive role of emotion dysregulation within the comorbidity between EDs and BPD.Methods: A sample of psychiatric outpatients (N = 872) collected from a longitudinal study spanning the mid-1990s to 2015 completed the Structured Clinical Interview for DSM-IV for Axis I Disorders as well as a measure of emotion regulation strategies, the Difficulties in Emotion Regulation Scale, in order to assess overall functioning.Results: In a regression analysis, BPD was significantly predicted by emotion regulation deficits and was strongly related to categories of emotion dysregulation. EDs were not significantly predicted by emotion regulation deficits but did predict BPD diagnoses (B = -0.14, P < .001). Overall, BPD demonstrated strong relationships to emotion regulation deficits.Conclusions: Results indicate that targeted treatment focusing on emotion regulation deficits may be particularly indicated with co-occurring BPD and ED diagnoses.
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Trastorno de Personalidad Limítrofe , Comorbilidad , Regulación Emocional , Trastornos de Alimentación y de la Ingestión de Alimentos , Humanos , Trastorno de Personalidad Limítrofe/psicología , Trastorno de Personalidad Limítrofe/epidemiología , Femenino , Adulto , Masculino , Trastornos de Alimentación y de la Ingestión de Alimentos/psicología , Trastornos de Alimentación y de la Ingestión de Alimentos/epidemiología , Estudios Longitudinales , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
AIM: The aim of the study was to identify the clinical significance of anxiety in those with depression, the Diagnostic and Statistical Manual of Mental Disorders 5th edition (DSM-5) defined criteria for an anxious distress specifier for major depressive disorder (MDD). The Clinically Useful Depression Outcome Scale (CUDOS) supplemented with questions for the DSM-5 anxious distress specifier (CUDOS-A) is a self-report instrument to assess the clinical significance of anxiety in addition to assess symptoms and the severity of depression. This study aimed to evaluate the psychometric properties of the Japanese version of the CUDOS-A. METHODS: An observational, prospective study was conducted with 131 MDD outpatients and 200 healthy controls. The Japanese version of the CUDOS-A, along with other measures, was administered to assess depressive symptoms, anxiety, social function, and biological rhythm. Reliability and validity analyses were performed, including internal consistency, test-retest reliability, convergent validity, and contrasted-groups validity. RESULTS: The Japanese version of the CUDOS-A demonstrated excellent internal consistency (Cronbach's alpha = 0.96) and test-retest reliability (ICC = 0.78). Significant positive correlations were found between the CUDOS-A and measures of depression, anxiety, social function, and biological rhythm (all, p < 0.001), supporting its convergent validity. The CUDOS-A effectively differentiated between patients with MDD and healthy controls (p < 0.001), indicating good contrasted-groups validity. CONCLUSIONS: The Japanese version of the CUDOS-A is a useful measure for research and for clinical practice, enabling the efficient assessment of anxious distress in individuals with depression.
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T cell acute lymphoblastic leukemia (T-ALL) is an aggressive immature T cell cancer. Mutations in IL7R have been analyzed genetically, but downstream effector functions such as STAT5A and STAT5B hyperactivation are poorly understood. Here, we studied the most frequent and clinically challenging STAT5BN642H driver in T cell development and immature T cell cancer onset and compared it with STAT5A hyperactive variants in transgenic mice. Enhanced STAT5 activity caused disrupted T cell development and promoted an early T cell progenitor-ALL phenotype, with upregulation of genes involved in T cell receptor (TCR) signaling, even in absence of surface TCR. Importantly, TCR pathway genes were overexpressed in human T-ALL and mature T cell cancers and activation of TCR pathway kinases was STAT5 dependent. We confirmed STAT5 binding to these genes using ChIP-Seq analysis in human T-ALL cells, which were sensitive to pharmacologic inhibition by dual STAT3/5 degraders or ZAP70 tyrosine kinase blockers in vitro and in vivo. We provide genetic and biochemical proof that STAT5A and STAT5B hyperactivation can initiate T-ALL through TCR pathway hijacking and suggest similar mechanisms for other T cell cancers. Thus, STAT5 or TCR component blockade are targeted therapy options, particularly in patients with chemoresistant clones carrying STAT5BN642H.
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Leucemia-Linfoma Linfoblástico de Células T Precursoras , Animales , Humanos , Ratones , Ratones Transgénicos , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Tirosina Quinasas , Receptores de Antígenos de Linfocitos T/genética , Transducción de Señal , Factor de Transcripción STAT5/genéticaRESUMEN
Women are predominantly diagnosed with BPD, with studies estimating a 3:1 female-to-male diagnostic ratio in clinical settings. Previous studies present conflicting findings regarding gender-level criterion differences, with some indicating differences in contradictory criteria. These studies primarily utilize outpatient samples, highlighting gaps in the literature. Thus, the current study investigates gender-level criterion differences, functioning, and impairment within a novel, partial hospital sample. Participants included (a) a sample of 1,153 individuals from the total population of partial hospital patients regardless of BPD diagnosis and (b) 365 BPD-positive patients who were assessed via semistructured clinical interview and provided consent for data collection during the intake process. Results indicated that (a) women endorsed higher relationship instability than men and (b) there were no significant differences in level of functioning across the gender subsamples. Examining gender differences in BPD symptomatology has clinical implications in improving recognition and addressing potential biases associated with men and mental health.
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Trastorno de Personalidad Limítrofe , Humanos , Masculino , Femenino , Trastorno de Personalidad Limítrofe/diagnóstico , Trastorno de Personalidad Limítrofe/epidemiología , Trastorno de Personalidad Limítrofe/psicología , Factores Sexuales , Pacientes Internos , Pacientes AmbulatoriosRESUMEN
Temporal regulation of super-enhancer (SE) driven transcription factors (TFs) underlies normal developmental programs. Neuroblastoma (NB) arises from an inability of sympathoadrenal progenitors to exit a self-renewal program and terminally differentiate. To identify SEs driving TF regulators, we use all-trans retinoic acid (ATRA) to induce NB growth arrest and differentiation. Time-course H3K27ac ChIP-seq and RNA-seq reveal ATRA coordinated SE waves. SEs that decrease with ATRA link to stem cell development (MYCN, GATA3, SOX11). CRISPR-Cas9 and siRNA verify SOX11 dependency, in vitro and in vivo. Silencing the SOX11 SE using dCAS9-KRAB decreases SOX11 mRNA and inhibits cell growth. Other TFs activate in sequential waves at 2, 4 and 8 days of ATRA treatment that regulate neural development (GATA2 and SOX4). Silencing the gained SOX4 SE using dCAS9-KRAB decreases SOX4 expression and attenuates ATRA-induced differentiation genes. Our study identifies oncogenic lineage drivers of NB self-renewal and TFs critical for implementing a differentiation program.
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Diferenciación Celular , Regulación Neoplásica de la Expresión Génica , Neuroblastoma , Factores de Transcripción SOXC , Tretinoina , Neuroblastoma/metabolismo , Neuroblastoma/genética , Neuroblastoma/patología , Tretinoina/farmacología , Tretinoina/metabolismo , Diferenciación Celular/efectos de los fármacos , Diferenciación Celular/genética , Factores de Transcripción SOXC/metabolismo , Factores de Transcripción SOXC/genética , Humanos , Animales , Línea Celular Tumoral , Ratones , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Autorrenovación de las Células/efectos de los fármacos , Autorrenovación de las Células/genética , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/genética , Linaje de la Célula/genética , Factor de Transcripción GATA2/metabolismo , Factor de Transcripción GATA2/genética , Sistemas CRISPR-Cas , Proteína Proto-Oncogénica N-Myc/metabolismo , Proteína Proto-Oncogénica N-Myc/genética , Proliferación Celular/efectos de los fármacos , Proliferación Celular/genéticaRESUMEN
OBJECTIVES: To examine the reliability and validity of a semi-structured interview assessing the features of the DSM-5 mixed features specifier. Our goal was to develop an instrument that could be used for both diagnostic and severity measurement purposes. METHODS: Four hundred fifty-nine psychiatric patients in a depressive episode were interviewed by a trained diagnostic rater who administered semi-structured interviews including the DSM-5 Mixed Features Specifier Interview (DMSI). We examined the inter-rater reliability and psychometric properties of the DMSI. The patients were rated on clinician rating scales of depression, anxiety, and irritability, and measures of psychosocial functioning, suicidality, and family history of bipolar disorder. RESULTS: The DMSI had excellent joint-interview interrater reliability. More than twice as many patients met the DSM-5 mixed features specifier criteria during the week before the assessment than for the majority of the episode (9.4% vs. 3.9%). DMSI total scores were more highly correlated with a clinician-rated measure of manic symptoms than with measures of depression and anxiety. More patients with bipolar depression met the mixed features specifier than patients with MDD. Amongst patients with MDD, those with mixed features more frequently had a family history of bipolar disorder, were more frequently diagnosed with anxiety disorders, attention deficit disorder, and borderline personality disorder, more frequently had attempted suicide, and were more severely depressed, anxious, and irritable. CONCLUSION: The DMSI is a reliable and valid measure of the presence of the DSM-5 mixed features specifier in depressed patients as well as the severity of the features of the specifier.
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Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here, we show that dysregulated STAT3 in ALCL cooccupies enhancers with master transcription factors BATF3, IRF4, and IKZF1 to form a core regulatory circuit that establishes and maintains the malignant cell state in ALCL. Critical downstream targets of this network in ALCL cells include the protooncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The core autoregulatory transcriptional circuitry activity is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. Thus, activation of STAT3 provides the crucial link between aberrant tyrosine kinase signaling and the core transcriptional machinery that drives tumorigenesis and creates therapeutic vulnerabilities in ALCL.