Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.     

All tyrosine kinase inhibitor-resistant chronic myelogenous cells are highly sensitive to Ponatinib

The advent of tyrosine kinase inhibitor (TKI) therapy has considerably improved the survival of patients suffering chronic myelogenous leukemia (CML). Indeed, inhibition of BCR-ABL by imatinib, dasatinib or nilotinib triggers durable responses in most patients suffering from this disease. Moreover, resistance to imatinib due to kinase domain mutations can be generally circumvented using dasatinib or nilotinib, but the multi-resistant T315I mutation that is insensitive to these TKIs, remains to date a major clinical problem. In this line, ponatinib (AP24534) has emerged as a promising therapeutic option in patients with all kinds of BCR-ABL mutations, especially the T315I one. However and surprisingly, the effect of ponatinib has not been extensively studied on imatinib-resistant CML cell lines. Therefore, in the present study, we used several CML cell lines with different mechanisms of resistance to TKI to evaluate the effect of ponatinib on cell viability, apoptosis and signaling. Our results show that ponatinib is highly effective on both sensitive and resistant CML cell lines, whatever the mode of resistance and also on BaF3 murine B cells carrying native BCR-ABL or T315I mutation. We conclude that ponatinib could be effectively used for all types of TKI-resistant patients.     

Depressive symptoms, major depressive episode and cognition in the elderly: the three-city study

OBJECTIVES: The relationship between depression and dementia in the elderly has been extensively studied but the tools used to define depressed subjects are heterogeneous between studies. The objective of this study was to examine the relationship between depression and cognitive performances by using multiple measures of depressive state. METHODS: A sample of 7,869 nondemented community-dwelling persons aged >or=65 years participated in the study. Depressive symptoms were evaluated by the Center for Epidemiological Study Depression Scale and the Mini-International Neuropsychiatric Interview was used to assess history of major depressive episodes (MDE). Cognitive function was evaluated by several tests including the Mini-Mental State Examination (MMSE), Trail Making Test, Isaacs Set Test and Benton Visual Retention Test. RESULTS: When studied in separate models, depressive symptoms were significantly related to lower cognitive performances for all neuropsychological tests after adjusting for potential confounders (p<0.0001), whereas subjects with current MDE had significantly lower performances in MMSE and Isaacs Set Test. When studied concomitantly, only high levels of depressive symptoms were related to lower cognitive performance, whereas existence of MDE (past or current) was no longer associated with cognitive performances. CONCLUSIONS: These data suggest that once current depressive symptoms are taken into account, major depression (past or current) is not associated with lower cognitive performances in a community-based sample of elderly people aged >or=65 years.     

AAV‐mediated gene delivery in Dp71‐null mouse model with compromised barriers

Formation and maintenance of the blood–retinal barrier (BRB) is required for proper vision and breaching of this barrier contributes to the pathology in a wide variety of retinal conditions such as retinal detachment and diabetic retinopathy. Dystrophin Dp71 being a key membrane cytoskeletal protein, expressed mainly in Müller cells, its absence has been related to BRB permeability through delocalization and down‐regulation of the AQP4 and Kir4.1 channels. Dp71‐null mouse is thus an excellent model to approach the study of retinal pathologies showing blood–retinal barrier permeability. We aimed to investigate the participation of Müller cells in the BRB and in the inner limiting membrane of Dp71‐null mice compared with wild‐type mice in order to understand how these barriers work in this model of permeable BRB. To this aim, we used an Adeno‐associated virus (AAV) variant, ShH10‐GFP, engineered to target Müller cells specifically. ShH10 coding GFP was introduced by intravitreal injection and Müller cell transduction was studied in Dp71‐null mice in comparison to wild‐type animals. We show that Müller cell transduction follows a significantly different pattern in Dp71‐null mice indicating changes in viral cell‐surface receptors as well as differences in the permeability of the inner limiting membrane in this mouse line. However, the compromised BRB of the Dp71‐null mice does not lead to virus leakage into the bloodstream when the virus is injected intravitreally – an important consideration for AAV‐mediated retinal gene therapy. GLIA 2014;62:468–476     

Physical and mental health status of former smokers and non-smokers patients with bipolar disorder

Objectives

Up to 70% individuals with bipolar disorder (BD) are lifetime tobacco smokers, a major modifiable risk factor for morbidity. However, quitting smoking is rarely proposed to individuals with BD, mainly because of fear of unfavorable metabolic or psychiatric changes. Evaluating the physical and mental impact of tobacco cessation is primordial. The aim of this study was to characterize the psychiatric and nonpsychiatric correlates of tobacco smoking status (never- vs. current vs. former smokers) in individuals with BD.

Methods

3860 individuals with ascertained BD recruited in the network of Fondamental expert centers for BD between 2009 and 2020 were categorized into current, former, and never tobacco smokers. We compared the sociodemographic and clinical characteristics assessed by standard instruments (e.g., BD type, current symptoms load, and non-psychiatric morbidity—including anthropometric and biological data) of the three groups using multinomial regression logistic models. Corrections for multiple testing were applied.

Results

Current smokers had higher depression, anxiety, and impulsivity levels than former and never-smokers, and also higher risk of comorbid substance use disorders with a gradient from never to former to current smokers—suggesting shared liability. Current smokers were at higher risk to have a metabolic syndrome than never-smokers, although this was only evidenced in cases, who were not using antipsychotics.

Conclusions

Tobacco smoking was associated with high morbidity level. Strikingly, as in the general population, quitting smoking seemed associated with their return to the never-smokers' levels. Our findings strongly highlight the need to spread strategies to treat tobacco addiction in the BD population.