Inhibition of Melanoma Growth by Small Molecules That Promote the Mitochondrial Localization of ATF2.

Inhibition of Melanoma Growth by Small Molecules that Promote the Mitochondrial Localization of ATF2.

Clin Cancer Res. 2013 Apr 15;
Varsano T, Lau E, Feng Y, Garrido M, Milan L, Heynen-Genel S, Hassig CA, Ronai ZA

PURPOSE: Effective therapy for malignant melanoma, the leading cause of death from skin cancer, remains an area of significant unmet need in oncology. The elevated expression of PKC? in advanced metastatic melanoma results in the increased phosphorylation of the transcription factor ATF2 on threonine 52, which causes its nuclear localization and confers its oncogenic activities. The nuclear-to-mitochondrial translocation of ATF2 following genotoxic stress promotes apoptosis, a function that is largely lost in melanoma cells, due to its confined nuclear localization. Therefore, promoting the nuclear export of ATF2, which sensitizes melanoma cells to apoptosis, represents a novel therapeutic modality. EXPERIMENTAL DESIGN: We conducted a pilot high-throughput screen of 3,800 compounds to identify small molecules that promote melanoma cell death by inducing the cytoplasmic localization of ATF2. The imaging-based ATF2 translocation assay was performed using UACC903 melanoma cells that stably express doxycycline-inducible GFP-ATF2. RESULTS: We identified 2 compounds (SBI-0089410 and SBI-0087702) that promoted the cytoplasmic localization of ATF2, reduced cell viability, inhibited colony formation, cell motility, anchorage-free growth, and increased mitochondrial membrane permeability. SBI-0089410 inhibited the TPA-induced membrane tranlocation of PKC isoforms, whereas both compounds decreased ATF2 phosphorylation by PKC? and ATF2 transcriptional activity. Overexpression of either constitutively active PKC? or phosphomimic mutant ATF2(T52E) attenuated the cellular effects of the compounds. CONCLUSION: The imaging-based high-throughput screen provides a proof-of-concept for the identification of small molecules that block the oncogenic addiction to PKC? signaling by promoting ATF2 nuclear export, resulting in mitochondrial membrane leakage and melanoma cell death. HubMed – addiction


The Psychometric Properties of the Personality Inventory for DSM-5 in an APA DSM-5 Field Trial Sample.

Assessment. 2013 Apr 15;
Quilty LC, Ayearst L, Chmielewski M, Pollock BG, Bagby RM

Section 3 of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) includes a hybrid model of personality pathology, in which dimensional personality traits are used to derive one of seven categorical personality disorder diagnoses. The Personality Inventory for DSM-5 (PID-5) was developed by the DSM-5 Personality and Personality Disorders workgroup and their consultants to produce a freely available instrument to assess the personality traits within this new system. To date, the psychometric properties of the PID-5 have been evaluated primarily in undergraduate student and community adult samples. In the current investigation, we extend this line of research to a psychiatric patient sample who participated in the APA DSM-5 Field Trial (Centre for Addiction and Mental Health site). A total of 201 psychiatric patients (102 men, 99 women) completed the PID-5 and the Revised NEO Personality Inventory (NEO PI-R). The internal consistencies of the PID-5 domain and facet trait scales were acceptable. Results supported the unidimensional structure of all trait scales but one, and the convergence between the PID-5 and analogous NEO PI-R scales. Evidence for discriminant validity was mixed. Overall, the current investigation provides support for the psychometric properties of this diagnostic instrument in psychiatric samples. HubMed – addiction


[Towards a comprehensive integration of obesity from an interdisciplinar perspective].

Nutr Hosp. 2012 Dec; 27(6): 1810-6
López Morales JL, Garcés de Los Fayos Ruiz EJ

This article summarizes the current situation of one of the most important XXI century epidemics. The high rates of obesity in all countries and specially in our country at early ages are worrying. Traditionally, investigations have focused on the most nutritional aspects, such us dietary factors, metabolism, calory intake and energy expenditure. However, other sciences -such as Psychology- point out new influencing factors, such as food addiction, depression, stress and anxiety. In this piece of work, more than 80 articles from all disciplines and different databases and related to obesity are analyzed, as well as a new theoretical approach is proposed to ensure a more accurate comprehension. The literature review shows the necessary evidence to introduce a new model of obesity named edorexia, and raise issues to be resolved in future research oriented from a multidisciplinary perspective. HubMed – addiction


Beer Flavor Provokes Striatal Dopamine Release in Male Drinkers: Mediation by Family History of Alcoholism.

Neuropsychopharmacology. 2013 Apr 15;
Oberlin BG, Dzemidzic M, Tran SM, Soeurt CM, Albrecht DS, Yoder KK, Kareken DA

Striatal dopamine (DA) is increased by virtually all drugs of abuse, including alcohol. However, drug-associated cues are also known to provoke striatal DA transmission- a phenomenon linked to the motivated behaviors associated with addiction. To our knowledge, no one has tested if alcohol’s classically-conditioned flavor cues, in the absence of a significant pharmacologic effect, are capable of eliciting striatal dopamine release in humans. Employing positron emission tomography (PET), we hypothesized that beer’s flavor alone can reduce the binding potential of [(11)C]raclopride (a reflection of striatal DA release) in the ventral striatum, relative to an appetitive flavor control. Forty-nine men, ranging from social to heavy drinking, mean age 25, with a varied family history of alcoholism underwent two [(11)C]raclopride PET scans: one while tasting beer, and one while tasting Gatorade®. Relative to the control flavor of Gatorade, beer flavor significantly increased self-reported desire to drink, and reduced [(11)C]raclopride binding potential, indicating that the alcohol-associated flavor cues induced dopamine release. Binding potential reductions were strongest in subjects with first-degree alcoholic relatives. These results demonstrate that alcohol-conditioned flavor cues can provoke ventral striatal dopamine release absent significant pharmacologic effects, and that the response is strongest in subjects with a greater genetic risk for alcoholism. Striatal DA responses to salient alcohol cues may thus be an inherited risk factor for alcoholism.Neuropsychopharmacology accepted article preview online, 15 April 2013; doi:10.1038/npp.2013.91. HubMed – addiction



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