Colorectal neoplastic emergencies in immunocompromised patients: preliminary result from the Web-based International Register of Emergency Surgery and Trauma (WIRES-T trial)

Association of advanced age, neoplastic disease and immunocompromission (IC) may lead to surgical emergencies. Few data exist about this topic. Present study reports the preliminary data from the WIRES-T trial about patients managed for colorectal neoplastic emergencies in immunocompromised patients. The required data were taken from a prospective observational international register. The study was approved by the Ethical Committee with approval n. 17575; ClinicalTrials.gov Identifier: NCT03643718. 839 patients were collected; 753 (80.7%) with mild-moderate IC and 86 (10.3%) with severe. Median age was 71.9 years and 73 years, respectively, in the two groups. The causes of mild-moderate IC were reported such malignancy (753-100%), diabetes (103-13.7%), malnutrition (26-3.5%) and uremia (1-0.1%), while severe IC causes were steroids treatment (14-16.3%); neutropenia (7-8.1%), malignancy on chemotherapy (71-82.6%). Preoperative risk classification were reported as follow: mild-moderate: ASA 1-14 (1.9%); ASA 2-202 (26.8%); ASA 3-341 (45.3%); ASA 4-84 (11.2%); ASA 5-7 (0.9%); severe group: ASA 1-1 patient (1.2%); ASA 2-16 patients (18.6%); ASA 3-41 patients (47.7%); ASA 4-19 patients (22.1%); ASA 5-3 patients (3.5%); lastly, ASA score was unavailable for 105 cases (13.9%) in mild-moderate group and in 6 cases (6.9%) in severe group. All the patients enrolled underwent urgent/emergency surgery Damage control approach with open abdomen was adopted in 18 patients. Mortality was 5.1% and 12.8%, respectively, in mild-moderate and severe groups. Long-term survival data: in mild-moderate disease-free survival (median, IQR) is 28 (10-91) and in severe IC, it is 21 (10-94). Overall survival (median, IQR) is 44 (18-99) and 26 (20-90) in mild-moderate and severe, respectively; the same is for post-progression survival (median, IQR) 29 (16-81) and 28, respectively. Univariate and multivariate analyses showed as the only factor influencing mortality in mild-moderate and severe IC is the ASA score. Colorectal neoplastic emergencies in immunocompromised patients are more frequent in elderly. Sigmoid and right colon are the most involved. Emergency surgery is at higher risk of complication and mortality; however, management in dedicated emergency surgery units is necessary to reduce disease burden and to optimize results by combining oncological and acute care principles. This approach may improve outcomes to obtain clinical advantages for patients like those observed in elective scenario. Lastly, damage control approach seems feasible and safe in selected patients

Importation des Colicines a travers l'Enveloppe d'Escherichia Coli

SIGLEINIST T 76451 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

In Pursuit of the American Dream: How Social Class Affects Future Possible Selves

In today’s society, do people believe they can personally achieve the American Dream, no matter their social class upbringing? In seven studies, we examined this question using the novel framework of social class possible selves. More specifically, we examined how high-aiming individuals’ social class possible selves are as a measure of future hoped-for, expected, and feared levels of education, occupational prestige, income, and subjective social class rank. We also examine how traditionally independent American cultural values will also be representative of future social class possible selves. Furthermore, we aimed to address how social class possible selves are shaped, examining family social class as an important predictor of social class possible selves and cultural values, as well as social mobility beliefs, system justification beliefs, collective social class self-esteem, and optimism as potential moderators. In addition, we addressed how much individuals believe in their social class possible selves by measuring perceptions of their efficaciousness and distance from the current self. Finally, we sought to establish the motivational power of social class possible selves on career attainment behaviors. We find social class possible selves represent distinct conceptualizations of social class in the future and are also represented by different levels of cultural values. Further, these possible selves all are predicted by family social class, though expected social class possible selves are the most strongly associated with class upbringing. In addition, expected selves are perceived as more likely to occur and closer to the present self. Family social class has differential effects on the efficacy and distance of these selves. Finally, we show that social class possible selves lead individuals to apply to opportunities that are in line with their expected levels of future income

In Pursuit of the American Dream: How Social Class Affects Future Possible Selves

In today’s society, do people believe they can personally achieve the American Dream, no matter their social class upbringing? In seven studies, we examined this question using the novel framework of social class possible selves. More specifically, we examined how high-aiming individuals’ social class possible selves are as a measure of future hoped-for, expected, and feared levels of education, occupational prestige, income, and subjective social class rank. We also examine how traditionally independent American cultural values will also be representative of future social class possible selves. Furthermore, we aimed to address how social class possible selves are shaped, examining family social class as an important predictor of social class possible selves and cultural values, as well as social mobility beliefs, system justification beliefs, collective social class self-esteem, and optimism as potential moderators. In addition, we addressed how much individuals believe in their social class possible selves by measuring perceptions of their efficaciousness and distance from the current self. Finally, we sought to establish the motivational power of social class possible selves on career attainment behaviors. We find social class possible selves represent distinct conceptualizations of social class in the future and are also represented by different levels of cultural values. Further, these possible selves all are predicted by family social class, though expected social class possible selves are the most strongly associated with class upbringing. In addition, expected selves are perceived as more likely to occur and closer to the present self. Family social class has differential effects on the efficacy and distance of these selves. Finally, we show that social class possible selves lead individuals to apply to opportunities that are in line with their expected levels of future income

MicroRNAs in Neurocognitive Dysfunctions: New Molecular Targets for Pharmacological Treatments?

International audienceBACKGROUND: Neurodegenerative and cognitive disorders are multifactorial diseases (i.e., involving neurodevelopmental, genetic, age or environmental factors) characterized by an abnormal development that affects neuronal function and integrity. Recently, an increasing number of studies revealed that the dysregulation of microRNAs (miRNAs) may be involved in the etiology of cognitive disorders as Alzheimer, Parkinson, and Huntington's diseases, Schizophrenia and Autism spectrum disorders.METHODS: From an extensive search in bibliographic databases of peer-reviewed research literature, we identified relevant published studies related to specific key words such as memory, cognition, neurodegenerative disorders, neurogenesis and miRNA. We then analysed, evaluated and summerized scientific evidences derived from these studies.RESULTS: We first briefly summarize the basic molecular events involved in memory, a process inherent to cognitive disease, and then describe the role of miRNAs in neurodevelopment, synaptic plasticity and memory. Secondly, we provide an overview of the impact of miRNA dysregulation in the pathogenesis of different neurocognitive disorders, and lastly discuss the feasibility of miRNA-based therapeutics in the treatment of these disorders.CONCLUSION: This review highlights the molecular basis of neurodegenerative and cognitive disorders by focusing on the impact of miRNAs dysregulation in these pathological phenotypes. Altogether, the published reports suggest that miRNAs-based therapy could be a viable therapeutic alternative to current treatment options in the future

Pharmacomodulation of microRNA Expression in Neurocognitive Diseases: Obstacles and Future Opportunities

International audienceGiven the importance of microRNAs (miRNAs) in modulating brain functions and their implications in neurocognitive disorders there are currently significant efforts devoted in the field of miRNA-based therapeutics to correct and/or to treat these brain diseases. The observation that miRNA 29a/b-1 cluster, miRNA 10b and miRNA 7, for instance, are frequently deregulated in the brains of patients with neurocognitive diseases and in animal models of Alzheimer, Huntington’s and Parkinson’s diseases, suggest that correction of miRNA expression using agonist or antagonist miRNA oligonucleotides might be a promising approach to correct or even to cure such diseases. The encouraging results from recent clinical trials allow envisioning that pharmacological approaches based on miRNAs might, in a near future, reach the requirements for successful therapeutic outcomes and will improve the healthcare of patients with brain injuries or disorders. This review will focus on the current strategies used to modulate pharmacological function of miRNA using chemically modified oligonucleotides. We will then review the recent literature on strategies to improve nucleic acid delivery across the blood-brain barrier which remains a severe obstacle to the widespread application of miRNA therapeutics to treat brain diseases. Finally, we provide a state-of-art of current preclinical research performed in animal models for the treatment of neurocognitive disorders using miRNA as therapeutic agents and discuss future developments of miRNA therapeutics

Occurrence and Origins of Cerium Dioxide and Titanium Dioxide Nanoparticles in the Loire River (France) by Single Particle ICP-MS and FEG-SEM Imaging

International audienceThe need to quantify engineered nanoparticles (ENPs) in the environment is due to the increasing incorporation of these particles in the daily products, which threatens human health and can possibly impact natural systems. Ceria NPs (CeO 2 NPs) and titanium dioxide NPs (TiO 2 NPs) are two of the most used ENPs in the world. In this study their occurrence was determined in river waters with accurate and relevant techniques such as single particle ICP-MS (spICPMS). In the Loire River (France), the variation of both CeO 2 NPs and TiO 2 NPs could be assessed locally, with an increase of the concentrations near a wastewater treatment plant (WWTP) outlet as well as in a lake connected to the river and dedicated to outdoor activities. In the upstream river water, supposedly less impacted by NPs, 6.4 ± 1.2 × 10 4 part mL −1 Ce-bearing and 13.4 ± 1.8 × 10 4 part mL −1 Ti-bearing particles were measured. These values increased to 33.9 ± 3.4 × 10 4 part mL −1 Ce-bearing and 80.3 ± 3.4 × 10 4 part mL −1 Ti-bearing particles near the WWTP outlet. Equivalent size for sphere distributions ranged from 24 nm to 70 nm for CeO 2 and from 80 nm to 500 nm for TiO 2 in the river water. In the lake, a raise of the concentrations has been observed with 38.3 ± 2.0 × 10 4 part mL −1 and 71.6 ± 2.1 × 10 4 part mL −1 containing Ce and Ti, respectively, with similar size distributions. FEG-SEM imaging confirms the occurrence of Ce-and Ti-bearing particles in the water samples. On the contrary, NPs seem to undergo strong heteroaggregation in the Loire river water. The Ce/La elemental ratios does not evolve from upstream to downstream the WWTP outlet, suggesting that a natural origin cannot be excluded to explain the increase observed in NPs number concentration. On the contrary, the Ce/La ratio increases in the outdoor activities center, which suggests the contribution of NPs potentially related to the cars parked nearby. Besides, elemental ratios Ti/V and Ti/Y have been assessed to highlight an anthropogenic source of Ti in both sampling sites, possibly to the sunscreens used during the summer

Microwave Assisted Organic Synthesis (MAOS) of New Dispacamide A Derivatives Bearing a Thiazolinone Platform, Biological Assays on Inhibition of Protein Kinases and Cell Effects

International audienc

Physical interaction between neurofibromin and serotonin 5-HT6receptor promotes receptor constitutive activity

International audienceActive G protein-coupled receptor (GPCR) conformations not only are promoted by agonists but also occur in their absence, leading to constitutive activity. Association of GPCRs with intracellular protein partners might be one of the mechanisms underlying GPCR constitutive activity. Here, we show that serotonin 5 hydroxytryptamine 6 (5-HT6) receptor constitutively activates the Gs/adenylyl cyclase pathway in various cell types, including neurons. Constitutive activity is strongly reduced by silencing expression of the Ras-GTPase activating protein (Ras-GAP) neurofibromin, a 5-HT6 receptor partner. Neurofibromin is a multidomain protein encoded by the NF1 gene, the mutation of which causes Neurofibromatosis type 1 (NF1), a genetic disorder characterized by multiple benign and malignant nervous system tumors and cognitive deficits. Disrupting association of 5-HT6 receptor with neurofibromin Pleckstrin Homology (PH) domain also inhibits receptor constitutive activity, and PH domain expression rescues 5-HT6 receptor-operated cAMP signaling in neurofibromin-deficient cells. Furthermore, PH domains carrying mutations identified in NF1 patients that prevent interaction with the 5-HT6 receptor fail to rescue receptor constitutive activity in neurofibromin-depleted cells. Further supporting a role of neurofibromin in agonist-independent Gs signaling elicited by native receptors, the phosphorylation of cAMP-responsive element-binding protein (CREB) is strongly decreased in prefrontal cortex of Nf1+/− mice compared with WT mice. Moreover, systemic administration of a 5-HT6 receptor inverse agonist reduces CREB phosphorylation in prefrontal cortex of WT mice but not Nf1+/− mice. Collectively, these findings suggest that disrupting 5-HT6 receptor–neurofibromin interaction prevents agonist-independent 5-HT6 receptor-operated cAMP signaling in prefrontal cortex, an effect that might underlie neuronal abnormalities in NF1 patients