Impact of the substitution distribution and the interlayer distance on both the surface energy and the hydration energy for Pb-montmorillonite

International audienceThe understanding of the adsorption of charged species in swelling clays is of primary importance to optimise the capture of heavy metal ions in soils. Adsorption is expected to depend on the microscopic structure of the clay, which varies strongly with the origin and history (hydration-desorption cycles, temperature ...) of the sample. Then it is necessary to evaluate the distinct interaction energies between water molecules, interlayer cations and clay surfaces, taking into account the position of the substitutions in the clay layer. Here we propose an investigation of plausible structures of some Pb-montmorillonites differing by their interlayer distances, their layer charges and the distribution of substitutions in octahedral sheet from a modelling approach, looking at the evolution of the partial charges in these structures. Using a methodology previously developed in the simpler case of alkali cations, we also estimate the surface energy in the dry state and then the details of the hydration energy for the cation and for the clay layer to interpret the capacity of ion adsorption in swelling clays to capture heavy metals. We conclude from our calculations that a cell structure with intermediate layer charge (close to 0.5 per unit cell) is probably the best candidate to allow the capture of the Pb2+ as interlayer cations considering the electrostatic effect. The hydration process of the cation appears as the most energetic part of the hydration of swelling clays compared to the interactions with the layer, but the cation mobility is limited since the hydration process is not complete. This means that the heavy metal ions, present in the interlayer space, will be unable to diffuse and will be captured in the case of a low layer charge

A highly conductive nanostructured PEDOT polymer confined into the mesoporous MIL-100(Fe)

[EN] Despite the higher efficiency, larger color range and faster stimulus response of polymeric electrochromic materials, their poor cyclability strongly hampers their application in optoelectronics. As an original strategy to stabilize and further nanostructure these polymers, herein an efficient encapsulation and in situ polymerization inside highly porous metal-organic frameworks (MOFs) is reported. In particular, the successful accommodation of poly(3,4-ethylendioxythiophene) (PEDOT) and its partially oxidized polarons inside the mesopores of the nontoxic iron trimesate MIL-100(Fe) is convincingly proved by a large panel of experimental techniques. Remarkably, the polymer-MOF interaction occurring for entrapped PEDOT within the pores (deeply assessed by experimental and simulation methods) might be responsible for the enhanced electrical conductivity of the resulting PEDOT@MIL-100(Fe) composite when compared to the insulating MIL-100(Fe) and the conductive free PEDOT. Furthermore, it was possible to observe the electrochromic properties of the PEDOT@MIL-100(Fe) composite, achieving an improved stability and good cyclability as a consequence of the effective protection by the MOF matrix.This work was supported by a 2017 Leonardo Grant for Researchers and Cultural Creators, BBVA Foundation (IN[17]_CBB_QUI_0197). The work was also partially supported by IMDEA Energy and Raphuel project (ENE2016-79608-C2-1-R, MINECOAEI/FEDER, UE). PH acknowledges the Spanish Ramon y Cajal Programme (grant agreement no. 2014-16823). S. N. thanks the Spanish Ministerio de Educacion, Cultura y Deporte for Jose Castillejo mobility programme (CAS14/00067) and financial support by Fundacion Ramon Areces (XVIII Concurso Nacional para la Adjudicacion de Ayudas a la Investigacion en Ciencias de la Vida y de la Materia, 2016). We also thank the synchrotron Soleil for providing access to the Cristal beamline.Salcedo-Abraira, P.; Santiago-Portillo, A.; Atienzar Corvillo, PE.; Bordet, P.; Salles, F.; Guillou, N.; Elkaim, E.... (2019). A highly conductive nanostructured PEDOT polymer confined into the mesoporous MIL-100(Fe). Dalton Transactions. 48(26):9807-9817. https://doi.org/10.1039/c9dt00917eS980798174826P. M. S. Monk , R. J.Mortimer and D. R.Rosseinsky , Electrochromism: fundamentals and applications , VCH , 1995Kondalkar, V. V., Kharade, R. R., Mali, S. S., Mane, R. M., Patil, P. B., Patil, P. S., … Bhosale, P. N. (2014). Nanobrick-like WO3 thin films: Hydrothermal synthesis and electrochromic application. Superlattices and Microstructures, 73, 290-295. doi:10.1016/j.spmi.2014.05.039Patil, C. E., Tarwal, N. L., Jadhav, P. R., Shinde, P. S., Deshmukh, H. P., Karanjkar, M. M., … Patil, P. S. (2014). Electrochromic performance of the mixed V2O5–WO3 thin films synthesized by pulsed spray pyrolysis technique. 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Trials

Background The risk/benefit ratio of using statins for primary prevention of cardiovascular (CV) events in elderly people has not been established. The main objectives of the present study are to assess the cost-effectiveness of statin cessation and to examine the non-inferiority of statin cessation in terms of mortality in patients aged 75 years and over, treated with statins for primary prevention of CV events. Methods The “Statins in the elderly” (SITE) study is an ongoing 3-year follow-up, open-label comparative multi-centre, randomized clinical trial that is being conducted in two parallel groups in outpatient primary care offices. Participants meeting the following criteria are included: people aged 75 years and older being treated with statins as primary prevention for CV events, who provide informed consent. After randomization, patients in the statin-cessation strategy are instructed to withdraw their treatment. In the comparison strategy, patients continue their statin treatment at the usual dosage. The cost-effectiveness of the statin-cessation strategy compared to continuing statins will be estimated through the incremental cost per quality-adjusted life years (QALYs) gained at 36 months, from the perspective of the French healthcare system. Overall mortality will be the primary clinical endpoint. We assumed that the mortality rate at 3 years will be 15%. The sample size was computed to achieve 90% power in showing the non-inferiority of statin cessation, assuming a non-inferiority margin of 5% of the between-group difference in overall mortality. In total, the SITE study will include 2430 individuals. Discussion There is some debate on the value of statins in people over 75 years old, especially for primary prevention of CV events, due to a lack of evidence of their efficacy in this population, potential compliance-related events, drug-drug interactions and side effects that could impair quality of life. Data from clinical trials guide the initiation of medication therapy for primary or secondary prevention of CV disease but do not define the timing, safety, or risks of discontinuing the agents. The SITE study is one of the first to examine whether treatment cessation is a cost-effective and a safe strategy in people of 75 years and over, formerly treated with statins

A gene-expression profiling score for prediction of outcome in patients with follicular lymphoma: a retrospective training and validation analysis in three international cohorts

Patients with follicular lymphoma (FL) have heterogeneous outcomes. Predictor models able to distinguish, at diagnosis, patients at high versus low risk of progression are still needed. A training set of fresh-frozen tumour biopsies was prospectively obtained from 160 untreated patients with high-tumour-burden follicular lymphoma enrolled in the phase 3 randomised PRIMA trial, in which rituximab maintenance was evaluated after rituximab plus chemotherapy induction (median follow-up 6·6 years [IQR 6·0-7·0]). RNA of sufficient quality was obtained for 149 of 160 cases, and Affymetrix U133 Plus 2.0 microarrays were used for gene-expression profiling. We did a multivariate Cox regression analysis to identify genes with expression levels associated with progression-free survival independently of maintenance treatment in a subgroup of 134 randomised patients. Expression levels from 95 curated genes were then determined by digital expression profiling (NanoString technology) in 53 formalin-fixed paraffin-embedded samples of the training set to compare the technical reproducibility of expression levels for each gene between technologies. Genes with high correlation (>0·75) were included in an L2-penalised Cox model adjusted on rituximab maintenance to build a predictive score for progression-free survival. The model was validated using NanoString technology to digitally quantify gene expression in 488 formalin-fixed, paraffin-embedded samples from three independent international patient cohorts from the PRIMA trial (n=178; distinct from the training cohort), the University of Iowa/Mayo Clinic Lymphoma SPORE project (n=201), and the Barcelona Hospital Clinic (n=109). All tissue samples consisted of pretreatment diagnostic biopsies and were confirmed as follicular lymphoma grade 1-3a. The patients were all treated with regimens containing rituximab and chemotherapy, possibly followed by either rituximab maintenance or ibritumomab-tiuxetan consolidation. We determined an optimum threshold on the score to predict patients at low risk and high risk of progression. The model, including the multigene score and the threshold, was initially evaluated in the three validation cohorts separately. The sensitivity and specificity of the score for the prediction of the risk of lymphoma progression at 2 years were assessed on the combined validation cohorts. FINDINGS: In the training cohort, the expression levels of 395 genes were associated with a risk of progression. 23 genes reflecting both B-cell biology and tumour microenvironment with correlation coefficients greater than 0·75 between the two technologies and sample types were retained to build a predictive model that identified a population at an increased risk of progression (p<0·0001). In a multivariate Cox model for progression-free survival adjusted on rituximab maintenance treatment and Follicular Lymphoma International Prognostic Index 1 (FLIPI-1) score, this predictor independently predicted progression (adjusted hazard ratio [aHR] of the high-risk group compared with the low-risk group 3·68, 95% CI 2·19-6·17 [p<0·0001]). The 5-year progression-free survival was 26% (95% CI 16-43) in the high-risk group and 73% (64-83) in the low-risk group. The predictor performances were confirmed in each of the individual validation cohorts (aHR comparing high-risk to low-risk groups 2·57 [95% CI 1·65-4·01] in cohort 1; 2·12 [1·32-3·39] in cohort 2; and 2·11 [1·01-4·41] in cohort 3). In the combined validation cohort, the median progression-free survival was 3·1 years (95% CI 2·4-4·8) in the high-risk group and 10·8 years (10·1-not reached) in the low-risk group (p<0·0001). The risk of lymphoma progression at 2 years was 38% (95% CI 29-46) in the high-risk group and 19% (15-24) in the low-risk group. In a multivariate analysis, the score predicted progression-free survival independently of anti-CD20 maintenance treatment and of the FLIPI score (aHR for the combined cohort 2·30, 95% CI 1·72-3·07). INTERPRETATION: We developed and validated a robust 23-gene expression-based predictor of progression-free survival that is applicable to routinely available formalin-fixed, paraffin-embedded tumour biopsies from patients with follicular lymphoma at time of diagnosis. Applying this score could allow individualised therapy for patients according to their risk category

EZH2 alterations in follicular lymphoma: biological and clinical correlations

International audienceThe histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n = 55) and H3K27 methylation (n = 63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n = 46, gain n = 23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36–0.93, P = 0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies

Prognostic Significance of MYC Rearrangement and Translocation Partner in Diffuse Large B-Cell Lymphoma : A Study by the Lunenburg Lymphoma Biomarker Consortium

PURPOSE: MYC rearrangement (MYC-R) occurs in approximately 10% of diffuse large B-cell lymphomas (DLBCLs) and has been associated with poor prognosis in many studies. The impact of MYC-R on prognosis may be influenced by the MYC partner gene (immunoglobulin [IG] or a non-IG gene). We evaluated a large cohort of patients through the Lunenburg Lymphoma Biomarker Consortium to validate the prognostic significance of MYC-R (single-, double-, and triple-hit status) in DLBCL within the context of the MYC partner gene. METHODS: The study cohort included patients with histologically confirmed DLBCL morphology derived from large prospective trials and patient registries in Europe and North America who were uniformly treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy or the like. Fluorescence in situ hybridization for the MYC, BCL2, BCL6, and IG heavy and light chain loci was used, and results were correlated with clinical outcomes. RESULTS: A total of 5,117 patients were identified of whom 2,383 (47%) had biopsy material available to assess for MYC-R. MYC-R was present in 264 (11%) of 2,383 patients and was associated with a significantly shorter progression-free and overall survival, with a strong time-dependent effect within the first 24 months after diagnosis. The adverse prognostic impact of MYC-R was only evident in patients with a concurrent rearrangement of BCL2 and/or BCL6 and an IG partner (hazard ratio, 2.4; 95% CI, 1.6 to 3.6; P < .001). CONCLUSION: The negative prognostic impact of MYC-R in DLBCL is largely observed in patients with MYC double hit/triple-hit disease in which MYC is translocated to an IG partner, and this effect is restricted to the first 2 years after diagnosis. Our results suggest that diagnostic strategies should be adopted to identify this high-risk cohort, and risk-adjusted therapeutic approaches should be refined further

DNA damage in B and T lymphocytes of farmers during one pesticide spraying season

Purpose The effect of one pesticide spraying seasonon DNA damage was measured on B and T lymphocytesamong open-field farmers and controls.Methods At least two peripheral blood samples were collectedfrom each individual: one in a period without anypesticide application, several weeks after the last use (January,at period P0), and another in the intensive pesticidespraying period (May or June, at period P4). DNA damagewas studied by alkaline comet assay on isolated B or Tlymphocytes.Results Longitudinal comparison of DNA damageobserved at both P0 and P4 periods revealed a statisticallysignificant genotoxic effect of the pesticide spraying seasonin both B (P = 0.02) and T lymphocytes (P = 0.02) in exposed farmers. In contrast, non-farmers did not showany significant modifications. DNA damage levels in Band T lymphocytes were significantly higher in farmersthan in non-farmers during the P4 period (P = 0.003 andP = 0.001 for B and T lymphocytes, respectively) but notduring the P0 period. The seasonal effect observed amongfarmers was not correlated with either total farm area, farmarea devoted to crops or recent solar exposure. On average,farmers used pesticides for 21 days between P0 and P4.Between the two time points studied, there was a tendencyfor a potential effect of the number of days of fungicidetreatments (r2 = 0.43; P = 0.11) on T lymphocyte DNAdamage.Conclusions A genotoxic effect was found in lymphocytesof farmers exposed to pesticides, suggesting in particularthe possible implication of fungicides

The coming decade of digital brain research: a vision for neuroscience at the intersection of technology and computing

In recent years, brain research has indisputably entered a new epoch, driven by substantial methodological advances and digitally enabled data integration and modelling at multiple scales— from molecules to the whole brain. Major advances are emerging at the intersection of neuroscience with technology and computing. This new science of the brain combines high-quality research, data integration across multiple scales, a new culture of multidisciplinary large-scale collaboration and translation into applications. As pioneered in Europe’s Human Brain Project (HBP), a systematic approach will be essential for meeting the coming decade’s pressing medical and technological challenges. The aims of this paper are to: develop a concept for the coming decade of digital brain research, discuss this new concept with the research community at large, to identify points of convergence, and derive therefrom scientific common goals; provide a scientific framework for the current and future development of EBRAINS, a research infrastructure resulting from the HBP’s work; inform and engage stakeholders, funding organisations and research institutions regarding future digital brain research; identify and address the transformational potential of comprehensive brain models for artificial intelligence, including machine learning and deep learning; outline a collaborative approach that integrates reflection, dialogues and societal engagement on ethical and societal opportunities and challenges as part of future neuroscience research