Redeployment-based drug screening identifies the anti-helminthic niclosamide as anti-myeloma therapy that also reduces free light chain production

Despite recent therapeutic advancements, multiple myeloma (MM) remains incurable and new therapies are needed, especially for the treatment of elderly and relapsed/refractory patients. We have screened a panel of 100 off-patent licensed oral drugs for anti-myeloma activity and identified niclosamide, an anti-helminthic. Niclosamide, at clinically achievable non-toxic concentrations, killed MM cell lines and primary MM cells as efficiently as or better than standard chemotherapy and existing anti-myeloma drugs individually or in combinations, with little impact on normal donor cells. Cell death was associated with markers of both apoptosis and autophagy. Importantly, niclosamide rapidly reduced free light chain (FLC) production by MM cell lines and primary MM. FLCs are a major cause of renal impairment in MM patients and light chain amyloid and FLC reduction is associated with reversal of tissue damage. Our data indicate that niclosamides anti-MM activity was mediated through the mitochondria with rapid loss of mitochondrial membrane potential, uncoupling of oxidative phosphorylation and production of mitochondrial superoxide. Niclosamide also modulated the nuclear factor-κB and STAT3 pathways in MM cells. In conclusion, our data indicate that MM cells can be selectively targeted using niclosamide while also reducing FLC secretion. Importantly, niclosamide is widely used at these concentrations with minimal toxicity

Exploring the role of Emotional Intelligence on disorder eating psychopathology

Purpose: This study aims to explore the role of emotional intelligence (EI) and specific facets that may underpin the aetiology of disordered eating attitudes and behaviours, as a means to understand what aspects of these deficits to target within treatments. Methods: Participants were recruited from the UK and Ireland. Among the sample of 355 participants, 84% were women and 16% were men. Regarding age, 59% were between 18 and 29, 30% were between 30 and 49, and 11% were 50 or older. Using a cross-sectional design, participants completed the Schutte Self-Report Emotional Intelligence Test to measure levels of trait EI and The Eating Attitudes Test (EAT-26) as a measure of eating disorder risk and presence of disordered eating attitudes. Results: EAT-26 scores were negatively correlated with total EI scores and with the following EI subscales: appraisal of own emotions, regulation of emotions, utilization of emotions, and optimism. Also, compared to those without an eating disorder history, participants who reported having had an eating disorder had significantly lower total EI scores and lower scores on four EI subscales: appraisal of others emotions, appraisal of own emotions, regulation of emotions, and optimism. Conclusions: Considering these findings, EI (especially appraisal of own emotions, regulation of emotions, and optimism) may need to be addressed by interventions and treatments for eating disorders

Neuroanatomical Pattern of Mitochondrial Complex I Pathology Varies between Schizophrenia, Bipolar Disorder and Major Depression

BACKGROUND:Mitochondrial dysfunction was reported in schizophrenia, bipolar disorderand major depression. The present study investigated whether mitochondrial complex I abnormalities show disease-specific characteristics. METHODOLOGY/PRINCIPAL FINDINGS:mRNA and protein levels of complex I subunits NDUFV1, NDUFV2 and NADUFS1, were assessed in striatal and lateral cerebellar hemisphere postmortem specimens and analyzed together with our previous data from prefrontal and parieto-occipital cortices specimens of patients with schizophrenia, bipolar disorder, major depression and healthy subjects. A disease-specific anatomical pattern in complex I subunits alterations was found. Schizophrenia-specific reductions were observed in the prefrontal cortex and in the striatum. The depressed group showed consistent reductions in all three subunits in the cerebellum. The bipolar group, however, showed increased expression in the parieto-occipital cortex, similar to those observed in schizophrenia, and reductions in the cerebellum, yet less consistent than the depressed group. CONCLUSIONS/SIGNIFICANCE:These results suggest that the neuroanatomical pattern of complex I pathology parallels the diversity and similarities in clinical symptoms of these mental disorders

Factorial validity of the Toronto Alexithymia Scale (TAS-20) in clinical samples: A critical examination of the literature and a psychometric study in anorexia nervosa

There is extensive use of the 20-item Toronto Alexithymia Scale (TAS-20) in research and clinical practice in anorexia nervosa (AN), though it is not empirically established in this population. This study aims to examine the factorial validity of the TAS-20 in a Portuguese AN sample (N = 125), testing four different models (ranging from 1 to 4 factors) that were identified in critical examination of existing factor analytic studies. Results of confirmatory factor analysis (CFA) suggested that the three-factor solution, measuring difficulty identifying (DIF) and describing feelings (DDF), and externally oriented thinking (EOT), was the best fitting model. The quality of measurement improves if two EOT items (16 and 18) are eliminated. Internal consistency of EOT was low and decreased with age. The results provide support for the factorial validity of the TAS-20 in AN. Nevertheless, the measurement of EOT requires some caution and may be problematic in AN adolescents.Center for Psychology at the University of Porto, Portuguese Science Foundation (FCT UID/PSI/00050/2013) and EU FEDER through COMPETE 2020 program (POCI-01-0145-FEDER-007294info:eu-repo/semantics/acceptedVersio

A psychophysiological investigation of the interplay between orienting and executive control during stimulus conflict: A heart rate variability study

Background It has been hypothesized that resting state cardiac vagal activity (CVA) - an indicator of parasympathetic nervous system activity - is a specific psychophysiological marker of executive control function. Here, we propose an alternative hypothesis - that CVA is associated with early stage attention orientation, promoting the flexible uptake of new information, on which the later operation of such executive control functions depends. We therefore predicted that CVA would predict the interaction between orienting and executive control. This was tested using the revised version of the Attention Network Test (ANT-R) that was developed to distinguish between orienting and executive attention during a stimulus conflict task. Methods Healthy adults (N = 48) performed the ANT-R and their resting CVA was measured over a 5 min period using ECG recordings. Results Multiple regression analyses indicated that, when other factors were controlled for, CVA was more strongly associated with the interaction between the orienting and executive control terms than with either factor individually. Conclusion Higher levels of CVA are specifically implicated in the modulation of executive control by intrinsic orientation operating at early stages of conflict detection. These initial findings of higher CVA on orienting attention in conflict detection need to be replicated in larger samples

Le programme RaDiCo (Rare Disease Cohorts) : construction et suivi de e-cohortes nationales et internationales

Les professionnels impliqués dans les maladies rares (MR), ont mis en avant un besoin critique de construire des cohortes nationales ou internationales multidisciplinaires afin d’aborder plus efficacement certaines questions scientifiques et médicoéconomiques. Objectif Le programme RaDiCo a pour objectifs :– la création d’une plate-forme opérationnelle nationale pour développer des e-cohortes MR répondant à de stricts critères d’excellence ;– le lancement d’e-cohortes MR sélectionnées par un appel d’offre national 2014.Matériel et méthodes Le programme RaDiCo est un programme national du Plan d’investissement d’Avenir, développé à l’Inserm U933, soutenu par l’ANR. La collecte se fait via REDCap, applicationweb sécurisée avec une interface intuitive et contrôle qualité du circuit des données. Les objectifs de ces cohortes sont de :– décrire l’histoire naturelle des MRs étudiées ;– établir des corrélations phénotype-génotype ;– élucider leur physiopathologie ;– identifier de nouvelles pistes thérapeutiques ;– évaluer leur impact sociétal et médico-économique ;– identifier les patients éligibles pour de nouvelles approches thérapeutiques.Résultats Le programme a permis la création ex nihilo d’une plate-forme assimilable à une infrastructure : avec mutualisation des connaissances, des savoir-faire, des métiers et des outils nécessaires à la création d’une base de données MR partagée ;interopérable ; fondée sur le « cloud computing », web sécurisée, conforme au RGPD ; avec un suivi continu de la qualité des données et de leur cohérence ; permettant aux patients de saisir leurs propres données (Qualité de Vie, dispositifs médicaux connectés,.) ; adaptée aux échanges avec le SNDS et le Health Data Hub (Fig. 1). Il a permis le lancement de 13 cohortes couvrant 67 MR dans des champs très différents : les anomalies congénitales de l’œil, la maladie de Still, le syndrome « Low Phospholipid-Associated Cholelithiasis (LPAC) », la cystinose, le syndrome d’Alport, les maladies dermatologiques rares, des formes monogéniques rares de déficience intellectuelle, les pathologies d’empreinte, les mucopolysaccharidoses, les dyskinésies ciliaires primitives, les paralysies périodiques, les pneumopathies interstitielles diffuses et le syndrome d’Ehlers-Danlos vasculaire (Fig. 2). Fin mars 2021, 6342 patients ont été inclus à partir de 183 sitesfranc¸ ais et étrangers (Fig. 3). Des partenariats public/privés ont permis de mettre en place le suivi de traitements spécifiques de 2 affections, soit en post-inscription soit en ré-inscription. Au plan national, RaDiCo est un acteur clé du 3e Plan National MR ; recommandé par la Haute Autorité de Santé auprès des industriels pour évaluer l’impact de médicaments MR en vie réelle. Discussion Les atouts de cette plateforme sont la flexibilité, l’interopérabilité et la facilité à partager les données recueillies permettant de construire de nouvelles cohortes. Au plan européen, 3 cohortes ont une extension européenne ; les coordonnateurs de cohortes sont impliqués dans les réseaux européens de référence (ERNs). RaDiCo est partenaire du programme européen « European Joint Program ». Conclusion RaDiCo a développé des e-cohortes et industrialisé les procédures de manière à pouvoir inclure de nouvelles maladiesrares. Des partenariats industriels et académiques ont été mis en œuvre et une implication forte dans le montage du projet Inserm « France Cohortes » assurera sa pérennité