Introduction: Although B-cell acute lymphoblastic leukemia (B-cell ALL) survival rates have improved in recent years, Hispanic children continue to have poorer survival rates. There are few tools available to identify at the time of diagnosis whether the patient will respond to induction therapy. Our goal was to identify predictive biomarkers of treatment response, which could also serve as prognostic biomarkers of death, by identifying methylated and differentially expressed genes between patients with positive minimal residual disease (MRD+) and negative minimal residual disease (MRD-). Methods: DNA and RNA were extracted from tumor blasts separated by immunomagnetic columns. Illumina MethlationEPIC and mRNA sequencing assays were performed on 13 bone marrows from Hispanic children with B-cell ALL. Partek Flow was used for transcript mapping and quantification, followed by differential expression analysis using DEseq2. DNA methylation analyses were performed with Partek Genomic Suite and Genome Studio. Gene expression and differential methylation were compared between patients with MRD-/- and MRD+/+ at the end of induction chemotherapy. Overexpressed and hypomethylated genes were selected and validated by RT-qPCR in samples of an independent validation cohort. The predictive ability of the genes was assessed by logistic regression. Survival and Cox regression analyses were performed to determine the association of genes with death. Results: DAPK1, BOC, CNKSR3, MIR4435-2HG, CTHRC1, NPDC1, SLC45A3, ITGA6, and ASCL2 were overexpressed and hypomethylated in MRD+/+ patients. Overexpression was also validated by RT-qPCR. DAPK1, BOC, ASCL2, and CNKSR3 can predict refractoriness, but MIR4435-2HG is the best predictor. Additionally, higher expression of MIR4435-2HG increases the probability of non-response, death, and the risk of death. Finally, MIR4435-2HG overexpression, together with MRD+, are associated with poorer survival, and together with overexpression of DAPK1 and ASCL2, it could improve the risk classification of patients with normal karyotype. Conclusion: MIR4435-2HG is a potential predictive biomarker of treatment response and death in children with B-cell ALL.
Altered DNA methylation (DNAm) patterns of discoidin domain receptor 1 (DDR1) have been found in the blood and brain of patients with schizophrenia (SCZ) and the brain of patients with bipolar disorder (BD). Childhood trauma (CT) is associated with changes in DNAm that in turn are related to suicidal behavior (SB) in patients with several psychiatric disorders. Here, using MassARRAY® technology, we studied 128 patients diagnosed with BD in remission and 141 healthy controls (HCs) to compare leukocyte DDR1 promoter DNAm patterns between patients and HCs and between patients with and without SB. Additionally, we investigated whether CT was associated with DDR1 DNAm and mediated SB. We found hypermethylation at DDR1 cg19215110 and cg23953820 sites and hypomethylation at cg14279856 and cg03270204 sites in patients with BD compared to HCs. Logistic regression models showed that hypermethylation of DDR1 cg23953820 but not cg19215110 and CT were risk factors for BD, while cg14279856 and cg03270204 hypomethylation were protective factors. In patients, CT was a risk factor for SB, but DDR1 DNAm, although associated with CT, did not mediate the association of CT with SB. This is the first study demonstrating altered leukocyte DDR1 promoter DNAm in euthymic patients with BD. We conclude that altered DDR1 DNAm may be related to immune and inflammatory mechanisms and could be a potential blood biomarker for the diagnosis and stratification of psychiatric patients.
BACKGROUND: Schizophrenic symptoms are known to segregate into reality distortion, negative and disorganization syndromes, but the correlates of these syndromes with regional brain structural change are not well established. Cognitive impairment is a further clinical feature of schizophrenia, whose brain structural correlates are the subject of conflicting findings. METHODS: 165 patients with schizophrenia were rated for symptoms using the PANSS, and cognitive impairment was indexed by estimated premorbid-current IQ discrepancy. Cortical volume was measured using surface-based morphometry in the patients and in 50 healthy controls. Correlations between clinical and cognitive measures and cortical volume were examined using whole-brain FreeSurfer tools. RESULTS: No clusters of volume reduction were seen associated with reality distortion or disorganization. Negative symptom scores showed a significant inverse correlation with volume in a small cluster in the left medial orbitofrontal gyrus. Larger estimated premorbid-current IQ discrepancies were associated with clusters of reduced cortical volume in the left precentral gyrus and the left temporal lobe. The cluster of association with negative symptoms disappeared when estimated premorbid-current IQ discrepancy was controlled for. CONCLUSIONS: This study does not provide support for an association between brain structural abnormality and reality distortion or disorganization syndromes in schizophrenia. The cluster of volume reduction found in the left medial orbitofrontal cortex correlated with negative symptoms may have reflected the association between this class of symptoms and cognitive impairment. The study adds to existing findings of an association between cognitive impairment and brain structural changes in the disorder.
Cognitive Dysfunction , Schizophrenia , Humans , Schizophrenia/complications , Schizophrenia/diagnostic imaging , Brain , Frontal Lobe , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/etiology , Temporal Lobe , Magnetic Resonance Imaging
Schizophrenia may represent a trade-off in the evolution of human-specific ontogenetic mechanisms that guide neurodevelopment. Human Accelerated Regions (HARs) are evolutionary markers functioning as neurodevelopmental transcription enhancers that have been associated with brain configuration, neural information processing, and schizophrenia risk. Here, we have investigated the influence of HARs' polygenic load on neuroanatomical measures through a case-control approach (128 patients with schizophrenia and 115 controls). To this end, we have calculated the global schizophrenia Polygenic Risk Score (Global PRSSZ) and that specific to HARs (HARs PRSSZ). We have also estimated the polygenic burden restricted to the HARs linked to transcriptional regulatory elements active in the foetal brain (FB-HARs PRSSZ) and the adult brain (AB-HARs PRSSZ). We have explored the main effects of the PRSs and the PRSs x diagnosis interactions on brain regional cortical thickness (CT) and surface area (SA). The results indicate that a higher FB-HARs PRSSZ is associated with patients' lower SA in the lateral orbitofrontal cortex, the superior temporal cortex, the pars triangularis and the paracentral lobule. While noHARs-derived PRSs show an effect on the risk, our neuroanatomical findings suggest that the human-specific transcriptional regulation during the prenatal period underlies SA variability, highlighting the role of these evolutionary markers in the schizophrenia genomic architecture.
Schizophrenia , Adult , Humans , Schizophrenia/genetics , Brain/diagnostic imaging , Prefrontal Cortex , Multifactorial Inheritance , Gene Expression Regulation
BACKGROUND: The negative symptoms of schizophrenia have been proposed to reflect prefrontal cortex dysfunction. However, this proposal has not been consistently supported in functional imaging studies, which have also used executive tasks that may not capture key aspects of negative symptoms such as lack of volition. METHOD: Twenty-four DSM-5 schizophrenic patients with high negative symptoms (HNS), 25 with absent negative symptoms (ANS) and 30 healthy controls underwent fMRI during performance of the Computerized Multiple Elements Test (CMET), a task designed to measure poor organization of goal directed behaviour or 'goal neglect'. Negative symptoms were rated using the PANSS and the Clinical Assessment Interview for Negative Symptoms (CAINS). RESULTS: On whole brain analysis, the ANS patients showed no significant clusters of reduced activation compared to the healthy controls. In contrast, the HNS patients showed hypoactivation compared to the healthy controls in the left anterior frontal cortex, the right dorsolateral prefrontal cortex (DLPFC), the anterior insula bilaterally and the bilateral inferior parietal cortex. When compared to the ANS patients, the HNS patients showed reduced activation in the left anterior frontal cortex, the left DLPFC and the left inferior parietal cortex. After controlling for disorganization scores, differences remained in clusters in the left anterior frontal cortex and the bilateral inferior parietal cortex. CONCLUSIONS: This study provides evidence that reduced prefrontal activation, perhaps especially in the left anterior frontal cortex, is a brain functional correlate of negative symptoms in schizophrenia. The simultaneous finding of reduced inferior parietal cortex activation was unexpected, but could reflect this region's involvement in cognitive control, particularly the 'regulative' component of this.
Schizophrenia , Schizophrenic Psychology , Goals , Humans , Magnetic Resonance Imaging/methods , Prefrontal Cortex/diagnostic imaging
Objetivo:Determinar los factores asociados al estrés laboral en las enfermeras de dos hospitales de la ciudad de Cartagena. Metodología: Se realizó un estudio analítico de corte transversal.La población correspondió a 156 enfermeras y enfermeros de los servicios de Urgencia, Hospitalización, UCI Adulto, Cirugía, Consulta Externa de dos hospitales de la ciudad de Cartagena. Para la recolección de información se utilizó la versión española del instrumento"TheNursing Stress Scale" (NSS), que valora siete factores relacionados con el ambiente físico, el ambiente psicológico y dos relacionados con el ambiente social en el hospital. Para el análisis de los datos se aplicó estadística descriptiva, se realizó análisis bivariado utilizando la probabilidad Kruskall Wallis y U Mann Whitney para estimar diferencias significativas de promedios entre variables. Resultados: Participaron en el estudio 156 enfermerasy enfermeros de dos hospitales de la ciudad de Cartagena, con promedio de edad de 33.2 años, el 94,2% (147) pertenecen al género femenino. La prevalencia de nivel alto de estrés correspondió a 33.9% (53) de los encuestados.Son variables asociadas al estrés ser menor de 30 años, tener pareja, tener más de un hijo, laborar en la consulta externa, tener un contrato a término fijo, estar vinculado a la empresa por más de dos años y tener más de cinco años de experiencia en el cargo. Conclusión: La presencia de estrés en los profesionales se asocia principalmente a factores personales y laborales como los servicios en que se trabaja y el tipo de contratación.
Objective: To determine the factors associated with work stress in nurses at two hospitals in the city of Cartagena. Methods: We performed across-sectional analytical study. The population fell to 156 nurses Emergency Services, Hospital, Adult ICU, Surgery, Outpatient, two hospitals in the city of Cartagena. For data collect on we used the Spanish version of the instrument "The Nursing Stress Scale" (NSS), which assesses seven factors related to the physical environment, the psychological environment and two related to the social environmentin the hospital. For the analysis of the data using descriptive statistics, we conducted bivariate analyzes using probability Kruskal Wallis and Mann Whitney U to estimate significant differences between variables averages. Results:The study involved 156 nursesat two hospitals inthe city of Cartagena, with a mean age of 33.2 years, 94.2% (147) are female. Thehighprevalence of stress corresponded to 33.9% (53) of respondents. Variables are associated with stress, age less than 30 years, having a partner, having more than one childin the outpatient work, have afixed term contract, be linked to the company for more than two years and have more than five years of experience in office.> Conclusion: The presence of stress in professionals is mainly associated with personal and work factors such as services in which they work and the type of contract.
