Distinguishing Originality from Creativity in ADHD: An Assessment of Creative Personality, Self-Perception, and Cognitive Style among Attention-Deficit/Hyperactivity Disorder Adults

Debates over whether Attention-Deficit/Hyperactivity Disorder (ADHD) relates to high levels of creativity have been hampered by a lack of rigor when defining creativity. The purpose of the present study was to go beyond the rhetoric by empirically investigating creative personality, creative self-perception, and cognitive style among 49 ADHD adults. Comparative analysis to studies of non-ADHD samples revealed distinctive tendencies: A mean group score of 115.71 (SD=18.02) on the Kirton Adaption-Innovation Inventory (KAI) indicated preferences for originality, nonconformity, paradigm-breaking, and low efficiency that was over one standard deviation higher than average non-ADHD population scores. Combined inattentive/hyperactiveimpulsive subtypes (n=20) scored 124.30 (SD=12.96). Ideator tendencies on Puccio’s FourSight indicated preferences for generating novel ideas and overlooking details. Adjective Check List (ACL) scores were slightly elevated on the Domino Creative Personality and Gough Creativity scales, but more so on the Change scale, indicating a tendency to seek novelty and avoid routine. Creative self-perception was high, with 85.71% reporting themselves as more creative than average. Although their dispositions toward originality might benefit creativity, it might be undermined by their disinclination for effectiveness necessary for full-fledged creativity. Results may help clinicians distinguish maladaptive ADHD behaviors from concomitant behaviors that might play a valuable role in creativity

Tackling the methylome: recent methodological advances in genome-wide methylation profiling

DNA methylation of promoter CpG islands is strongly associated with gene silencing and is known as a frequent cause of loss of expression of tumor suppressor genes, as well as other genes involved in tumor formation. DNA methylation of driver genes is very likely outnumbered by the number of methylated passenger genes, though these can be useful as tumor markers. Much of what is known about the importance of DNA methylation in cancer was gained through small- and moderate-scale analysis of gene promoters and tumor samples. A much better understanding of the role of DNA methylation in cancer, either as a marker of disease or as an active driver of tumorigenesis, will likely be gained from genome-wide studies of this modification in normal and malignant cells. This goal has become more attainable with the recent introduction of large-scale genome analysis methodologies and these have been modified to allow for investigation of DNA methylation. Several research groups have been formed to coordinate efforts and apply these methodologies to decipher the methylome of healthy and diseased tissues. In this article we review technological advances in genome-wide methylation profiling

Estimation de facteurs de Bayes entre modèles dynamiques non linéaires à espace d'état

aeres : ACLInternational audienceLes modèles non linéaires à espace d'état sont utilisés de façon croissante pour représenter de nombreux systèmes dynamiques stochastiques et pour les contrôler. De nouveaux outils de filtrage particulaire sont maintenant disponibles pour l'identification de ces modèles. Il n'en va pas de même pour le problème de leur sélection statistique car les vraisemblances associées sont le plus souvent non accessibles et d'estimation difficile. Ceci exclut a priori les critères classiques de comparaison de modèles de type Akaïke et compromet l'utilisation des méthodes performantes basées sur l'estimation d'un facteur de Bayes par simulations MCMC. Cette Note propose un estimateur convergent non paramétrique d'un facteur de Bayes pour ces modèles, comme application directe de ces nouveaux filtres particulaires. The use of nonlinear state space models in the study and control of stochastic dynamic systems is regularly growing. With the new generation of particle filters, efficient filtering methods are now available for the identification of these models. However their statistical selection is still an open problem because of the frequent nonaccessibility of the related likelihoods and the intricate estimation of the latter. This rules out all the usual model comparison information criteria as Akaïke's and unfavour also the efficient methods relying on Bayes factor estimation by MCMC simulations

Impact of decitabine on immunohistochemistry expression of the putative tumor suppressor genes FHIT, WWOX, FUS1 and PTEN in clinical tumor samples.

BackgroundSince tumor suppressor gene function may be lost through hypermethylation, we assessed whether the demethylating agent decitabine could increase tumor suppressor gene expression clinically. For fragile histidine triad (FHIT), WW domain-containing oxidoreductase (WWOX), fused in sarcoma-1 (FUS1) and phosphatase and tensin homolog (PTEN), immunohistochemistry scores from pre- and post-decitabine tumor biopsies (25 patients) were correlated with methylation of the long interspersed nuclear element-1 (LINE-1) repetitive DNA element (as a surrogate for global DNA methylation) and with tumor regression.ResultsWith negative staining pre-decitabine (score = 0), the number of patients converting to positive staining post-decitabine was 1 of 1 for FHIT, 3 of 6 for WWOX, 2 of 3 for FUS1 and 1 of 10 for PTEN. In tumors with low pre-decitabine tumor suppressor gene scores (≤150), expression was higher post-treatment in 8 of 8 cases for FHIT (P = 0.014), 7 of 17 for WWOX (P = 0.0547), 7 of 12 for FUS1 (P = 0.0726), and 1 of 16 for PTEN (P = 0.2034). If FHIT, WWOX and FUS1 were considered together, median pre- versus post-decitabine scores were 60 versus 100 (P = 0.0002). Overall, tumor suppressor gene expression change did not correlate with LINE-1 demethylation, although tumors converting from negative to positive had a median decrease in LINE-1 methylation of 24%, compared to 6% in those not converting (P = 0.069). Five of 15 fully evaluable patients had reductions in tumor diameter (range 0.2% to 33.4%). Of these, three had simultaneous increases in three tumor suppressor genes (including the two patients with the greatest tumor regression) compared to 2 of 10 with tumor growth (P = 0.25).ConclusionsIn tumors with low tumor suppressor gene expression, decitabine may be associated with increased expression of the tumor suppressor genes FHIT, FUS1, and WWOX, but not PTEN

Targeting DNA methylation

Abstract Two nucleoside inhibitors of DNA methylation, azacitidine and decitabine, are now standard of care for the treatment of the myelodysplastic syndrome, a deadly form of leukemia. These old drugs, developed as cytotoxic agents and nearly abandoned decades ago were resurrected by the renewed interest in DNA methylation. They have now provided proof of principle for epigenetic therapy, the final chapter in the long saga to provide legitimacy to the field of epigenetics in cancer. But challenges remain; we don't understand precisely how or why the drugs work or stop working after an initial response. Extending these promising findings to solid tumors faces substantial hurdles from drug uptake to clinical trial design.We do not know yet how to select patients for this therapy and how to move it from life extension to cure. The epigenetic potential of DNA methylation inhibitors may be limited by other epigenetic mechanisms that are also worth exploring as therapeutic targets. But the idea of stably changing gene expression in vivo has transformative potential in cancer therapy and beyond

Downregulation of Histone H3 Lysine 9 Methyltransferase G9a Induces Centrosome Disruption and Chromosome Instability in Cancer Cells

Modifications of the histone amino-terminal tails affect access of regulatory factors and complexes to chromatin and thereby influence biological processes. Cancer cells are characterized by prominent epigenetic dysregulation, including histone modifications. However, the functional roles of the histone methyltransferases (HMT) in cancer remain unclear.We studied RNAi-based inhibition (knockdown, KD) of 2 different H3K9 HMTs, SUV39H1 and G9a. Knockdown of the 2 HMTs in PC3 cancer cell line markedly inhibited cell growth and caused profound morphological changes with loss of telomerase activity and shortened telomeres. SUV39H1 KD cells showed substantial increase in G2/M fraction. G9a KD cells showed increased DNA content (1.7-fold in 2 independent clones) compared with FACS analyses to control. Karyotype analyses showed that this was due to an increased number of chromosomes (from 61 to 102) in G9a KD cells compared to parental PC3. Intriguingly, we found abnormal centrosome morphology and number in about 25% of the G9a KD cells, while centrosomes were morphologically normal in control cells. Microarray analyses after KD of SUV39H1 or G9a showed very few genes up-regulated among the 39,000 genes. The silenced tumor-suppressor genes p16 and RASSF1A were not activated in KD cells.These data suggest that the 2 HMTs, SUV39H1 and G9a are required to perpetuate the malignant phenotype. Furthermore, G9a plays a critical role in regulating centrosome duplication presumably through chromatin structure rather than through affecting gene expression in cancer cells. Targeting these histone methyltransferases may be of therapeutic benefit in cancers

Phase I study of azacitidine and oxaliplatin in patients with advanced cancers that have relapsed or are refractory to any platinum therapy.

BackgroundDemethylation process is necessary for the expression of various factors involved in chemotherapy cytotoxicity or resistance. Platinum-resistant cells may have reduced expression of the copper/platinum transporter CTR1. We hypothesized that azacitidine and oxaliplatin combination therapy may restore platinum sensitivity. We treated patients with cancer relapsed/refractory to any platinum compounds (3 + 3 study design) with azacitidine (20 to 50 mg/m(2)/day intravenously (IV) over 15 to 30 min, D1 to 5) and oxaliplatin (15 to 30 mg/m(2)/day, IV over 2 h, D2 to 5) (maximum, six cycles). Platinum content, LINE1 methylation (surrogate of global DNA methylation), and CTR1 expression changes (pre- vs. post-treatment) were assessed. Drug pharmacokinetics were analyzed.ResultsThirty-seven patients were treated. No dose-limiting toxicity (DLT) was noted at the maximum dose. The most common adverse events were anemia and fatigue. Two (5.4%) patients had stable disease and completed six cycles of therapy. Oxaliplatin (D2) and azacitidine (D1 and 5) mean systemic exposure based on plasma AUCall showed dose-dependent interaction whereby increasing the dose of oxaliplatin reduced the mean azacitidine exposure and vice versa; however, no significant differences in other non-compartmental modeled parameters were observed. Blood samples showed universal reduction in global DNA methylation. In tumor samples, hypomethylation was only observed in four out of seven patients. No correlation between blood and tumor demethylation was seen. The mean cytoplasmic CTR1 score decreased. The pre-dose tumor oxaliplatin levels ranged from <0.25 to 5.8 μg/g tumor. The platinum concentration increased 3- to 18-fold. No correlation was found between CTR1 score and oxaliplatin level, which was found to have a trend toward correlation with progression-free survival.ConclusionsOxaliplatin and azacitidine combination therapy was safe. CTR1 expression was not correlated with methylation status or tissue platinum concentration