Synthesis of Multifunctional Polymersomes Prepared by Polymerization-Induced Self-Assembly

Polymersomes are an exciting modality for drug delivery due to their structural similarity to biological cells and their ability to encapsulate both hydrophilic and hydrophobic drugs. In this regard, the current work aimed to develop multifunctional polymersomes, integrating dye (with hydrophobic Nile red and hydrophilic sulfo-cyanine5-NHS ester as model drugs) encapsulation, stimulus responsiveness, and surface-ligand modifications. Polymersomes constituting poly(N-2-hydroxypropylmethacrylamide)-b-poly(N-(2-(methylthio)ethyl)acrylamide) (PHPMAm-b-PMTEAM) are prepared by aqueous dispersion RAFT-mediated polymerization-induced self-assembly (PISA). The hydrophilic block lengths have an effect on the obtained morphologies, with short chain P(HPMAm)16 affording spheres and long chain P(HPMAm)43 yielding vesicles. This further induces different responses to H2O2, with spheres fragmenting and vesicles aggregating. Folic acid (FA) is successfully conjugated to the P(HPMAm)43, which self-assembles into FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes. The FA-functionalized P(HPMAm)43-b-P(MTEAM)300 polymersomes entrap both hydrophobic Nile red (NR) and hydrophilic Cy5 dye. The NR-loaded FA-linked polymersomes exhibit a controlled release of the encapsulated NR dye when exposed to 10 mM H2O2. All the polymersomes formed are stable in human plasma and well-tolerated in MCF-7 breast cancer cells. These preliminary results demonstrate that, with simple and scalable chemistry, PISA offers access to different shapes and opens up the possibility of the one-pot synthesis of multicompartmental and responsive polymersomes

The rationale, design, and methods of a randomized, controlled trial to evaluate the efficacy and safety of an active strategy for the diagnosis and treatment of acute pulmonary embolism during exacerbations of chronic obstructive pulmonary disease

Introduction: Some previous studies have suggested a high prevalence of pulmonary embolism (PE) during exacerbations of chronic obstructive pulmonary disease (ECOPD). The SLICE trial aims to assess the efficacy and safety of an active strategy for the diagnosis and treatment of PE (vs usual care) in patients hospitalized because of ECOPD. Methods: SLICE is a phase III, prospective, international, multicenter, randomized, open-label, and parallel-group trial. A total of 746 patients hospitalized because of ECOPD will be randomized in a 1:1 fashion to receive either an active strategy for the diagnosis and anticoagulant treatment of PE or usual care (ie, standard care without any diagnostic test for diagnosing PE). The primary outcome is a composite of all-cause death, non-fatal (recurrent) venous thromboembolism (VTE), or readmission for ECOPD within 90 days after enrollment. Secondary outcomes are (a) death from any cause within 90 days after enrollment, (b) non-fatal (recurrent) VTE within 90 days after enrollment, (c) readmission within 90 days after enrollment, and (d) length of hospital stay. Results: Enrollment started in September 2014 and is expected to proceed until 2020. Median age of the first 443 patients was 71 years (interquartile range, 64-78), and 26% were female. Conclusions: This multicenter trial will determine the value of detecting PEs in patients with ECOPD. This has implications for COPD patient morbidity and mortality

Effect of a Pulmonary Embolism Diagnostic Strategy on Clinical Outcomes in Patients Hospitalized for COPD Exacerbation. A Randomized Clinical Trial

SLICE Trial Group.[Importance] Active search for pulmonary embolism (PE) may improve outcomes in patients hospitalized for exacerbations of chronic obstructive pulmonary disease (COPD).[Objective] To compare usual care plus an active strategy for diagnosing PE with usual care alone in patients hospitalized for COPD exacerbation.[Design, Setting, and Participants] Randomized clinical trial conducted across 18 hospitals in Spain. A total of 746 patients were randomized from September 2014 to July 2020 (final follow-up was November 2020).[Interventions] Usual care plus an active strategy for diagnosing PE (D-dimer testing and, if positive, computed tomography pulmonary angiogram) (n = 370) vs usual care (n = 367).[Main Outcomes and Measures] The primary outcome was a composite of nonfatal symptomatic venous thromboembolism (VTE), readmission for COPD, or death within 90 days after randomization. There were 4 secondary outcomes, including nonfatal new or recurrent VTE, readmission for COPD, and death from any cause within 90 days. Adverse events were also collected.[Results] Among the 746 patients who were randomized, 737 (98.8%) completed the trial (mean age, 70 years; 195 [26%] women). The primary outcome occurred in 110 patients (29.7%) in the intervention group and 107 patients (29.2%) in the control group (absolute risk difference, 0.5% [95% CI, −6.2% to 7.3%]; relative risk, 1.02 [95% CI, 0.82-1.28]; P = .86). Nonfatal new or recurrent VTE was not significantly different in the 2 groups (0.5% vs 2.5%; risk difference, −2.0% [95% CI, −4.3% to 0.1%]). By day 90, a total of 94 patients (25.4%) in the intervention group and 84 (22.9%) in the control group had been readmitted for exacerbation of COPD (risk difference, 2.5% [95% CI, −3.9% to 8.9%]). Death from any cause occurred in 23 patients (6.2%) in the intervention group and 29 (7.9%) in the control group (risk difference, −1.7% [95% CI, −5.7% to 2.3%]). Major bleeding occurred in 3 patients (0.8%) in the intervention group and 3 patients (0.8%) in the control group (risk difference, 0% [95% CI, −1.9% to 1.8%]; P = .99).[Conclusions and Relevance] Among patients hospitalized for an exacerbation of COPD, the addition of an active strategy for the diagnosis of PE to usual care, compared with usual care alone, did not significantly improve a composite health outcome. The study may not have had adequate power to assess individual components of the composite outcome.[Trial Registration] ClinicalTrials.gov Identifier: NCT02238639.Peer reviewe

A rare coding mutation in the MAST2 gene causes venous thrombosis in a French family with unexplained thrombophilia: The Breizh MAST2 Arg89Gln variant.

Rare variants outside the classical coagulation cascade might cause inherited thrombosis. We aimed to identify the variant(s) causing venous thromboembolism (VTE) in a family with multiple relatives affected with unprovoked VTE and no thrombophilia defects. We identified by whole exome sequencing an extremely rare Arg to Gln variant (Arg89Gln) in the Microtubule Associated Serine/Threonine Kinase 2 (MAST2) gene that segregates with VTE in the family. Free-tissue factor pathway inhibitor (f-TFPI) plasma levels were significantly decreased in affected family members compared to healthy relatives. Conversely, plasminogen activator inhibitor-1 (PAI-1) levels were significantly higher in affected members than in healthy relatives. RNA sequencing analysis of RNA interference experimental data conducted in endothelial cells revealed that, of the 13,387 detected expressed genes, 2,354 have their level of expression modified by MAST2 knockdown, including SERPINE1 coding for PAI-1 and TFPI. In HEK293 cells overexpressing the MAST2 Gln89 variant, TFPI and SERPINE1 promoter activities were respectively lower and higher than in cells overexpressing the MAST2 wild type. This study identifies a novel thrombophilia-causing Arg89Gln variant in the MAST2 gene that is here proposed as a new molecular player in the etiology of VTE by interfering with hemostatic balance of endothelial cells

[The optimal duration of anticoagulant treatment following pulmonary embolism].

International audienceThe optimal course of oral anticoagulant therapy is determined according to the risk of recurrent venous thromboembolism after stopping therapy and the risk of anticoagulant-related bleeding. Clinical risk factors appear to be important in predicting the risk of recurrence whereas the influence of biochemical and morphological tests is uncertain. The risk of recurrent venous thromboembolism is low when the initial episode was provoked by a reversible major risk factor (surgery): 3 months of anticoagulation is sufficient. Conversely, the risk is high when venous thromboembolism was unprovoked or associated with persistent risk factor (cancer): 6 months or more prolonged anticoagulation is necessary. After this first estimation, the duration of anticoagulation may be modulated according to the presence or absence of certain additional risk factors (major thrombophilia, chronic pulmonary hypertension, massive pulmonary embolism): 6 months if pulmonary embolism was provoked and 12 to 24 months if pulmonary embolism was unprovoked. If the risk of anticoagulant-related bleeding is high, the duration of anticoagulation should be shortened (3 months if pulmonary embolism was provoked and 3 to 6 months if it was unprovoked). Lastly, if pulmonary embolism occurred in association with cancer, anticoagulation should be conducted for 6 months or more if the cancer is active or treatment is on going. Despite an increasing knowledge of the risk factors for recurrent venous thromboembolism, a number of issues remain unresolved. Randomised trials comparing different durations of anticoagulation are needed

[Current protocols: foreword].

International audienc

Guided duration of anticoagulation after unprovoked venous thromboembolism using D-dimer testing.

International audienc

[Prolongation of oral anticoagulant treatment for eighteen months versus placebo at the decline of a first episode of idiopathic pulmonary embolism treated for six months: a randomized, multicentric, double blind trial. 2006 National PHRC (Hospital clinical research programme): "PADIS-EP/Prolongation of anticoagulant treatment for 18 months for a first episode of PE initially treated for 6 months"].

International audienc

Risque de maladie thrombo-embolique veineuse chez les membres de familles au premier degré de patients ayant une maladie thrombo-embolique veineuse idiopathique

Rationnel: Les patients ayant une maladie veineuse thrombo-embolique (MVTE) idiopathique ont un risque élevé de récidive thrombo-embolique et sont fréquemment porteurs d une thrombophilie héréditaire. Notre hypothèse scientifique est, qu en l absence de thrombophilie héréditaire détectable, ces patients ont en fait une thrombophilie encore non connue à ce jour. Objectif : Evaluer, chez les membres de la famille au premier degré de patients ayant une MVTE idiopathique, le risque de survenue d une première MVTE selon que les propositi sont porteurs ou non d une thrombophilie héréditaire. Si notre hypothèse est vraie, alors le risque familial de MVTE est identique, que les propositus présentent ou non une thrombophilie détectable. Méthodes: Etude transversale multicentrique internationale réalisée sur 1778 membres de la famille au premier degré de 348 patients (propositus) recrutés consécutivement pour une MVTE idiopathique objectivement diagnostiquée. Au moyen d un questionnaire prédéfini et standardisé , les membres de familles ont été classés comme ayant eu une MVTE certaine , MVTE incertaine et n ayant pas eu de MVTE . Tous les propositus ont été testés pour la mutation Leiden et la mutation G20210A sur le gène de la prothrombine. Résultats: En analyse multivariée, lorsque les MVTE incertaines sont classées comme pas de MVTE , nous observons une tendance à un risque accru de MVTE chez les membres de familles lorsque le propositus est porteur d une thrombophilie héréditaire (risque relatif de 1,52 [0,98 2,37], p = 0,06) ; lorsque les MVTE incertaines sont classées comme certaines , ce risque est proche de 1 (1,18 [0,87-1,60], p = 0,3). En revanche, quel que soit le niveau de précision du critère diagnostic de MVTE, le risque de MVTE est significativement accru chez les femmes au premier degré et d autant plus que le propositus est jeune. Conclusion: Chez les membres de famille au premier degré de patients ayant une MVTE idiopathique, le risque de MVTE est faiblement influencé par la présence d une thrombophilie héréditaire chez les propositus. Ce résultat plaide en faveur de notre hypothèse scientifique. Une des implications majeures est qu une prévention du risque de MVTE ne devrait pas être proposée qu aux seuls membres de famille de patients ayant une MVTE associée à une thrombophilie héréditaire détectableRational : In patients with idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high and a large proportion of these patients carry inherited thrombophilia. Our hypothesis is that patients with idiopathic VTE without detectable inherited thrombophilia have a genetic prothrombotic state not yet discovered. Objective : To evaluate the risk of VTE in first degree relatives of patients with idiopathic VTE and with or without inherited thrombophilia. If our hypothesis is true, this risk should be similar, with or without thrombophilia. Methods : In this international multicentre study, 1778 first degree relatives of 348 propositus with objectively diagnosed idiopathic VTE were included. Relatives were classified as having certain VTE , uncertain VTE or no VTE according to a predefined and standardised questionnaire. All the propositus were tested for the Leiden mutation and the G20210A prothrombin gene mutation. Results : In multivariate analysis, when uncertain VTE were classified as No VTE , we observed a trend of an increased risk of VTE in first degree relatives of probants with an inherited thrombophilia (relative risk of 1,52 [0,98 2,37], p = 0,06); when uncertain VTE were classified as certain VTE , the relative risk of VTE was closed to 1.0 (1,18 [0,87-1,60], p = 0,3). For each level of VTE diagnosis criteria precision, there was an increased risk of VTE in first degree relatives women and in relatives from younger probants. Conclusion : The presence of an inherited thrombophilia in patients with idiopathic VTE is weakly associated with an increased risk in their first degree relatives. This observation supports our scientific hypothesis. One the main implications of this study is that the prevention of VTE should not be proposed in only first degree relatives of patients with VTE and inherited thrombophiliaLYON1-BU.Sciences (692662101) / SudocSudocFranceF