The objective of this study was to develop a structured and transparent framework to rank emerging dietary practices. The first challenge was to rank simultaneously biological and chemical hazards ...using the same criteria whatever the nature of the hazard. For a list of dietary practices selected based on the results of a survey, hazard identification and health effect characterization was carried out. Taking only the top five practices led to the identification of 41 triplets “emerging dietary practice – hazard – health effect”, which highlights the complexity of scoring risk in food safety. A wide variety of hazards, including microbes, parasites, mycotoxins, allergens and other chemical compounds were considered together with a range of health effects such as foodborne pathogen disease, anaphylaxis, cancer, immunosuppression, endocrine disturbance, etc. The second challenge was to develop a framework easy to populate and run. The risk-ranking framework included eight criteria: five to describe the severity, three to describe the likelihood. All of them were informed by literature data and food safety agencies' reports, plus experts’ opinion. The PROMETHEE outranking MCDA technique, available in a R package, was implemented. This risk-ranking framework applied to the results of our small-scale survey revealed that consuming nuts on a regular basis could be the emerging dietary habit presenting the highest-risk score, due to the aflatoxin B1 hazard and its associated health effect (liver cancer). This risk-ranking framework requires however to be applied furthermore in other contexts to evaluate its robustness and identify opportunities for improvement. Once consolidated, this framework will be highly relevant for food safety authorities and policy makers to move forward transparent and evidence-informed decisions.
•A structured and transparent framework to rank food safety risks was developed.•The framework was run using the MCDA outranking PROMETHEE method.•Biological and chemical riks were assessed using the same set of criteria.•The risk-ranking framework was tested on emerging dietary practices in France.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective:
This study aimed to understand the associations between mindfulness, perceived stress, and work engagement in a very large sample of English-speaking adults, from 130 different countries. ...It also aimed to assess participants' self-reported changes following a 6-week mindfulness massive open online course (MOOC).
Methods:
Participants in the 6-week MOOC were invited to complete pre-post online surveys. Cross-sectional associations were assessed using univariate linear models, followed by structural equation models to test mediation pathways in baseline data (
N
= 16,697). Self-reported changes in mindfulness, stress and engagement following training were assessed using paired
t
-tests (
n
= 2,105).
Results:
Each standard deviation unit increase in mindfulness was associated with a 0.52 standard deviation unit decrease in perceived stress, and with 0.06 standard deviation unit increment in work engagement. 73% of the influence of mindfulness on engagement was direct. Following the mindfulness MOOC, participants reported higher mindfulness (
d
= 1.16), reduced perceived stress (
d
= 1.00) and a small improvement in work engagement (
d
= 0.29).
Conclusions:
Mindfulness was associated with lower perceived stress and higher work engagement in both cross-sectional and longitudinal analyses. These findings support mindfulness as a potentially protective and modifiable personal resource. The MOOC format offers a low cost, highly accessible means for extending the reach and potential benefits of mindfulness training to large numbers of people.
In chordates, the central nervous system arises from precursors that have distinct developmental and transcriptional trajectories. Anterior nervous systems are ontogenically associated with ...ectodermal lineages while posterior nervous systems are associated with mesoderm. Taking advantage of the well-documented cell lineage of ascidian embryos, we asked to what extent the transcriptional states of the different neural lineages become similar during the course of progressive lineage restriction. We performed single-cell RNA sequencing (scRNA-seq) analyses on hand-dissected neural precursor cells of the two distinct lineages, together with those of their sister cell lineages, with a high temporal resolution covering five successive cell cycles from the 16-cell to neural plate stages. A transcription factor binding site enrichment analysis of neural specific genes at the neural plate stage revealed limited evidence for shared transcriptional control between the two neural lineages, consistent with their different ontogenies. Nevertheless, PCA analysis and hierarchical clustering showed that, by neural plate stages, the two neural lineages cluster together. Consistent with this, we identified a set of genes enriched in both neural lineages at the neural plate stage, including miR-124, Celf3.a, Zic.r-b, and Ets1/2. Altogether, the current study has revealed genome-wide transcriptional dynamics of neural progenitor cells of two distinct developmental origins. Our scRNA-seq dataset is unique and provides a valuable resource for future analyses, enabling a precise temporal resolution of cell types not previously described from dissociated embryos.
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•scRNA-seq of hand-dissected ascidian neural lineages.•Transcriptional trajectories of neural lineages over five successive cell divisions.•Two distinct neural lineages become transcriptionally closer with time.•Pan-neural gene set identified.•The strongest statistical signal of convergence comes from a likely miRNA.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multipotential stem cells can be selected from the bone marrow by plastic adhesion, expanded, and cultured. They are able to differentiate not only into multiple cell types, including cartilage, ...bone, adipose and fibrous tissues, and myelosupportive stroma, but also into mesodermal (endothelium), neuroectodermal, or endodermal (hepatocytes) lineages. Our goal was to characterize the multipotential capacities of human mesenchymal stem cells (hMSCs) and to evaluate their ability to differentiate into insulin‐secreting cells in vitro. hMSCs were obtained from healthy donors, selected by plastic adhesion, and phenotyped by fluorescence‐activated cell sorter and reverse transcription–polymerase chain reaction analysis before and after infection with adenoviruses coding for mouse IPF1, HLXB9, and FOXA2 transcription factors involved early in the endocrine developmental pathway. We found that native hMSCs have a pluripotent phenotype (OCT4 expression and high telomere length) and constitutively express NKX6‐1 at a low level but lack all other transcription factors implicated in beta‐cell differentiation. In all hMSCs, we detected mRNA of cytokeratin 18 and 19, epithelial markers present in pancreatic ductal cells, whereas proconvertase 1/3 mRNA expression was detected only in some hMSCs. Ectopic expression of IPF1, HLXB9, and FOXA2 with or without islet coculture or islet‐conditioned medium results in insulin gene expression. In conclusion, our results demonstrated that in vitro human bone marrow stem cells are able to differentiate into insulin‐expressing cells by a mechanism involving several transcription factors of the beta‐cell developmental pathway when cultured in an appropriate microenvironment.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In chronic obstructive pulmonary disease (COPD), lung-infiltrating inflammatory cells secrete proteases and participate in elastin breakdown and genesis of elastin-derived peptides (EP). In the ...present study, we hypothesized that the pattern of T lymphocytes cytokine expression may be modulated by EP in COPD patients.
CD4
and CD8
T-cells, sorted from peripheral blood mononuclear cells (PBMC) collected from COPD patients (n = 29) and controls (n = 13) were cultured with or without EP. Cytokine expression in T-cell phenotypes was analyzed by multicolor flow cytometry, whereas desmosine concentration, a specific marker of elastin degradation, was measured in sera.
Compared with control, the percentage of IL-4 (Th2) producing CD4
T-cells was decreased in COPD patients (35.3 ± 3.4% and 26.3 ± 2.4%, respectively, p < 0.05), whereas no significant differences were found with IFN-γ (Th1) and IL-17A (Th17). Among COPD patients, two subpopulations were observed based on the percentage of IL-4 (Th2) producing CD4
T-cells, of which only one expressed high IL-4 levels in association with high levels of desmosine and strong smoking exposure (n = 7). Upon stimulation with VGVAPG, a bioactive EP motif, the percentage of CD4
T cells expressing IL-4 significantly increased in COPD patients (p < 0.05), but not in controls. The VGVAPG-induced increase in IL-4 was inhibited in the presence of analogous peptide antagonizing VGVAPG/elastin receptor (S-gal) interactions.
The present study demonstrates that the VGVAPG elastin peptide modulates CD4
T-cells IL-4 production in COPD. Monitoring IL-4 in circulating CD4
T-cells may help to better characterize COPD phenotypes and could open a new pharmacologic opportunity through CD4
T-cells stimulation via the VGVAPG/S-gal receptor in order to favor an anti-inflammatory response in those COPD patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aims
Intracoronary administration of autologous bone marrow cells (BMCs) leads to a modest improvement in cardiac function, but the effect on myocardial viability is unknown. The aim of this ...randomized multicentre study was to evaluate the effect of BMC therapy on myocardial viability in patients with decreased left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) and to identify predictive factors for improvement of myocardial viability.
Methods and results
One hundred and one patients with AMI and successful reperfusion, LVEF ≤45%, and decreased myocardial viability (resting Tl201-SPECT) were randomized to either a control group (n = 49) or a BMC group (n = 52). Primary endpoint was improvement of myocardial viability 3 months after AMI. Baseline mean LVEF measured by radionuclide angiography was 36.3 ± 6.9%. Bone marrow cell infusion was performed 9.3 ± 1.7 days after AMI. Myocardial viability improved in 16/47 (34%) patients in the BMC group compared with 7/43 (16%) in the control group (P = 0.06). The number of non-viable segments becoming viable was 0.8 ± 1.1 in the control group and 1.2 ± 1.5 in the BMC group (P = 0.13). Multivariate analysis including major post-AMI prognostic factors showed a significant improvement of myocardial viability in BMC vs. control group (P = 0.03). Moreover, a significant adverse role for active smoking (P = 0.04) and a positive trend for microvascular obstruction (P = 0.07) were observed.
Conclusion
Intracoronary autologous BMC administration to patients with decreased LVEF after AMI was associated with improvement of myocardial viability in multivariate-but not in univariate-analysis. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy and better define a group of patients that will benefit from this therapy.
Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier NCT00200707.
Stroke is the leading cause of disability in adults. Many current clinical trials use intravenous (IV) administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs). This autologous ...graft requires a delay for ex vivo expansion of cells. We followed microvascular effects and mechanisms of action involved after an IV injection of human BM-MSCs (hBM-MSCs) at a subacute phase of stroke. Rats underwent a transient middle cerebral artery occlusion (MCAo) or a surgery without occlusion (sham) at day 0 (D0). At D8, rats received an IV injection of 3 million hBM-MSCs or PBS-glutamine. In a longitudinal behavioral follow-up, we showed delayed somatosensory and cognitive benefits 4 to 7 weeks after hBM-MSC injection. In a separate longitudinal in vivo magnetic resonance imaging (MRI) study, we observed an enhanced vascular density in the ischemic area 2 and 3 weeks after hBM-MSC injection. Histology and quantitative polymerase chain reaction (qPCR) revealed an overexpression of angiogenic factors such as Ang1 and transforming growth factor-β1 (TGF-β1) at D16 in hBM-MSC-treated MCAo rats compared to PBS-treated MCAo rats. Altogether, delayed IV injection of hBM-MSCs provides functional benefits and increases cerebral angiogenesis in the stroke lesion via a release of endogenous angiogenic factors enhancing the stabilization of newborn vessels. Enhanced angiogenesis could therefore be a means of improving functional recovery after stroke.
Epidermal Growth Factor Receptor (EGFR) mutations, especially in-frame deletions in exon 19 (ΔLRE) and a point mutation in exon 21 (L858R) predict gefitinib sensitivity in patients with non-small ...cell lung cancer. Several methods are currently described for their detection but the gold standard for tissue samples remains direct DNA sequencing, which requires samples containing at least 50% of tumor cells.
We designed a pyrosequencing assay based on nested PCR for the characterization of theses mutations on formalin-fixed and paraffin-embedded tumor tissue.
This method is highly specific and permits precise characterization of all the exon 19 deletions. Its sensitivity is higher than that of "BigDye terminator" sequencing and enabled detection of 3 additional mutations in the 58 NSCLC tested. The concordance between the two methods was very good (97.4%). In the prospective analysis of 213 samples, 7 (3.3%) samples were not analyzed and EGFR mutations were detected in 18 (8.7%) patients. However, we observed a deficit of mutation detection when the samples were very poor in tumor cells.
pyrosequencing is then a highly accurate method for detecting ΔLRE and L858R EGFR mutations in patients with NSCLC when the samples contain at least 20% of tumor cells.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
"Replicative stress" is one of the main factors underlying neoplasia from its early stages. Genes involved in DNA synthesis may therefore represent an underexplored source of potential prognostic ...markers for cancer. To this aim, we generated gene expression profiles from two independent cohorts (France, n = 206; United Kingdom, n = 117) of patients with previously untreated primary breast cancers. We report here that among the 13 human nuclear DNA polymerase genes, DNA Polymerase θ (POLQ) is the only one significantly up-regulated in breast cancer compared with normal breast tissues. Importantly, POLQ up-regulation significantly correlates with poor clinical outcome (4.3-fold increased risk of death in patients with high POLQ expression), and this correlation is independent of Cyclin E expression or the number of positive nodes, which are currently considered as markers for poor outcome. POLQ expression provides thus an additional indicator for the survival outcome of patients with high Cyclin E tumor expression or high number of positive lymph nodes. Furthermore, to decipher the molecular consequences of POLQ up-regulation in breast cancer, we generated human MRC5-SV cell lines that stably overexpress POLQ. Strong POLQ expression was directly associated with defective DNA replication fork progression and chromosomal damage. Therefore, POLQ overexpression may be a promising genetic instability and prognostic marker for breast cancer.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The immune control of hepatitis B virus (HBV) infection is essential for viral clearance. Therefore, restoring functional anti–HBV immunity is a promising immunotherapeutic approach to treatment of ...chronic infection. Plasmacytoid dendritic cells (pDCs) play a crucial role in triggering antiviral immunity through their ability to capture and process viral antigens and subsequently induce adaptive immune responses. We investigated the potential of pDCs to trigger antiviral cellular immunity against HBV. We used a human leukocyte antigen A (HLA–A)*0201+ pDC line loaded with HLA–A*0201‐restricted peptides derived from hepatitis B core/hepatitis B surface (HBc/HBs) antigens to amplify specific CD8 T cells ex vivo from chronic HBV patients and established a Hepato‐HuPBL mouse model to address the therapeutic potential of the strategy in vivo. Stimulation of PBMCs or liver‐infiltrating lymphocytes from HLA–A*0201+ chronic HBV patients by HBc peptide‐loaded pDCs elicited up to 23.1% and 76.1% HBV‐specific CD8 T cells in 45.8% of cases. The specific T cells from the “responder” group secreted interferon‐γ, expressed CD107 upon restimulation, and efficiently lysed HBV antigen‐expressing hepatocytes. Circulating hepatitis B e antigen (HBeAg) was found to distinguish the group of patients not responding to the pDC stimulation. The therapeutic efficacy of the pDC vaccine was evaluated in immunodeficient NOD‐SCID β2m−/− mice reconstituted with HBV patients' PBMCs and xenotransplanted with human HBV‐transfected hepatocytes. Vaccination of Hepato–HuPBL mice with the HBc/HBs peptide–loaded pDCs elicited HBV‐specific T cells able to specifically lyse the transfected hepatocytes and reduce the systemic viral load. Conclusion: pDCs loaded with HBV–derived peptides can elicit functional virus‐specific T cells. HBeAg appears to be critical in determining the outcome of immunotherapies in chronic HBV patients. A pDC‐based immunotherapeutic approach could be of interest in attempts to restore functional antiviral immunity, which is critical for the control of the virus in chronic HBV patients. (HEPATOLOGY 2012;56:1706–1718)
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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