Dual effect of Algerian propolis on lung cancer: antitumor and chemopreventive effects involving antioxidant activity

The purpose of our study was to divulge the antiproliferative effect of an ethanolic extract of Algerian propolis (EEP) in the human lung adenocarcinoma cell line (A549) and reveal the chemopreventive role against benzo(a)pyrene-induced lung carcinogenesis in albino Wistar rats. Cytotoxicity of EEP was evaluated using the MTT assay and cell adhesion in A549 cells. Moreover, rats were given 25 mg/kg of propolis for 5 days before induction of experimental lung cancer by a single intraperitoneal dose of 200 mg/kg benzo(a)pyrene. Body weight, lung weight, lipid peroxidation, marker enzymes, and enzymatic and non-enzymatic antioxidants were estimated. The EEP demonstrated an inhibitory effect on proliferation of A549 at 24 and 72 hours in a dose-dependent manner and blocked adhesion of the cells by fibrinogen. Moreover, EEP reduced the oxidative stress generated by benzo(a)pyrene. The pre-treatment showed that enzymatic and non-enzymatic antioxidants increased and lipid peroxidation decreased. A histological analysis further supported these findings and showed a decrease in the number of side effects. These results are particularly important for both clinical applications of propolis and the possibility for its use as a potential chemotherapeutic agent

Repurposing chlorpromazine for anti-leukaemic therapy by nanoparticle encapsulation

Treatment of acute myeloid leukaemia (AML) relies on decades-old drugs, and while recent years have seen some breakthroughs, AML is still characterised by poor prognosis and survival rate. Drug repurposing can expedite the preclinical development of new therapies, and by nanocarrier encapsulation, the number of potentially viable drug candidates can be further expanded. The anti-psychotic drug chlorpromazine (CPZ) has been identified as a candidate for repurposing for AML therapy. Nanoencapsulation may improve the suitability of CPZ for the treatment of AML by reducing its effect on the central nervous system. Using the emulsion-evaporation technique, we have developed PEGylated PLGA nanoparticles loaded with CPZ for AML therapy. The nanoparticles were characterised to be between 150 and 300 nm by DLS, of spherical morphology by TEM, with a drug loading of at least 6.0% (w/w). After an initial burst release of adsorbed drug, the remaining 80% of the drug was retained in the PLGA nanoparticles for at least 24 h. The CPZ-loaded nanoparticles had equal cytotoxic potential towards AML cells to free CPZ, but acted more slowly, in line with the protracted drug release. Crucially, nanoparticles injected intravenously into zebrafish larvae did not accumulate in the brain, and nanoencapsulation also prevented CPZ from crossing an artificial membrane model. This demonstrates that the purpose for nanoencapsulation of CPZ is fulfilled, namely avoiding effects on the central nervous system while retaining the anti-AML activity of the drug.publishedVersio

Moving magnetoencephalography towards real-world applications with a wearable system

Imaging human brain function with techniques such as magnetoencephalography1 (MEG) typically requires a subject to perform tasks whilst their head remains still within a restrictive scanner. This artificial environment makes the technique inaccessible to many people, and limits the experimental questions that can be addressed. For example, it has been difficult to apply neuroimaging to investigation of the neural substrates of cognitive development in babies and children, or in adult studies that require unconstrained head movement (e.g. spatial navigation). Here, we develop a new type of MEG system that can be worn like a helmet, allowing free and natural movement during scanning. This is possible due to the integration of new quantum sensors2,3 that do not rely on superconducting technology, with a novel system for nulling background magnetic fields. We demonstrate human electrophysiological measurement at millisecond resolution whilst subjects make natural movements, including head nodding, stretching, drinking and playing a ball game. Results compare well to the current state-of-the-art, even when subjects make large head movements. The system opens up new possibilities for scanning any subject or patient group, with myriad applications such as characterisation of the neurodevelopmental connectome, imaging subjects moving naturally in a virtual environment, and understanding the pathophysiology of movement disorders

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Intéractions de la miltefosine avec la barrière intestinale (étude des mécanismes de capture et de transport sur un modèle in vitro de cellules CACO-2)

La miltéfosine (hexadecylphosphocholine, HePC) est une nouvelle molécule disponible pour le traitement de la leishmaniose viscérale. Elle a comme particularité et avantage majeur d'être active après une administration par voie orale. La voie orale est une voie d'administration de choix: elle est non invasive, souvent de faible coût et favorise l'observance du traitement. Le passage de la miltéfosine à travers la barrière intestinale est très peu décrit dans la littérature. Ce travail de thèse a donc comme objectif d'étudier les effets de la miltéfosine sur l'épithélium intestinal et de déterminer les mécanismes mis en jeu lors de sa capture et de son transport sur un modèle in vitro composé de cellules épithéliales Caco-2 en culture. Ces données ont été exploitées pour développer une bithérapie antileishmanienne administrée par voie orale: la potentialité de la miltéfosine à améliorer la biodisponibilité orale de l'amphotéricine B, un autre agent antileishmanien, a été évaluée.Miltefosine (hexadecylphosphocholine, HePC) has recently been developed for the treatment of visceral leishmaniasis. It has the particular advantage of being active after oral administration. The oral route is preferable because it is non invasive, is often less expensive and favours compliance with treatment. There is not much information in the literature about the passage of miltefosine across the intestinal barrier. Therefore, the aims of this thesis were to study the effects of miltefosine on the intestinal epithelium and to determine the mechanisms involved in its uptake and transport, using a model of Caco-2 cells in culture. The results were applied to the development of antileishmanial bitherapy by the oral route: the ability of miltefosine to improve the oral bioavailability of another antileishmanial agent, amphotericin B, was evaluated.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-Museum Hist.Naturelle (751052304) / SudocSudocFranceF

Formulation de liposomes d'interleukine-2 conventionnels ou à temps de circulation prolongé et spécifiques des cellules du système immunitaire

L'Interleukine-2 (IL-2) joue un rôle clef dans la réponse immunitaire ce qui lui confère de nombreux intérêts dans le traitement des cancers et du VIH. La demi-vie très courte de l'IL-2 après administration intraveineuse nécessite la mise en place de protocoles thérapeutiques lourds à l'origine d'effets secondaires importants. Parmi les stratégies envisagées pour diminuer ces effets indésirables, nous avons choisi de formuler des liposomes d'IL-2. Une méthode de dosage par fluorescence de l'IL-2 associée aux liposomes a tout d'abord été mise au point. Les effets, sur l'activité biologique', de l'IL-2, des conditions de formulation des liposomes et des interactions protéine-lipide ont été étudiées. L'objectif final de cette thèse a été de formuler des liposomes à temps de rémanence accrue et spécifiques des cellules du système immunitaire. Ces vecteurs permettraient d'allonger la demie vie de la protéine et de la libérer au contact des cellules cibles améliorant ainsi son efficacitéThe key role played by the cytokine Interleukin-2 (IL-2) in the immune response gives it great potential for the treatment of cancers and HW infection. However, the short haif-life ofIL-2 after intravenous administration means that large doses have to be given leading to serious side-effects. We have formulated liposomes containing IL-2 as one strategy for reducing these side-effects. We first developed a method based on the intrinsic fluorescence of IL-2 to measure its association with liposomes. The effect of the preparation conditions of liposomes on the biological activity of IL-2 and the nature of the lipid-protein interactions were studied. The ultimate aim of this work was to formulate long-circulating liposomes which were specifically targeted to cells of the immune system. This carrier system could increase the circulating haif-life of the protein and release it in the vicinity of the target cells, thus increasing its efficacy.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Mental health and houses in multiple occupation

Purpose – Previous research has established that there is a relationship between housing and mental health, however, understanding about how and why housing affects mental health is still limited. The purpose of this paper is to address this deficit by focusing on the experiences of residents of houses in multiple occupation (HMOs). Design/methodology/approach – Semi-structured interviews were carried out with 20 HMO residents who were asked about their housing career and experience of living in a HMO. Participants were recruited with assistance from community organisations and landlords. Findings – The physical properties and social environment of the property, as well as personal circumstances experienced prior to the move into the property, all influenced how mental health was affected. The authors identify and discuss in detail three key meditating factors: safety, control and identity which may affect how living in the property impacts the mental health of tenants. Practical implications – Good property management can lessen the potential harmful effects of living in a HMO. However, poorly run properties which house numerous vulnerable people may increase the risk of poor mental health due to attendant high levels of stress and possible risk of abuse. Originality/value – Based on the reports of HMO residents, the authors outline the key mediating processes through which living in HMOs may affect mental wellbeing, as well as illuminating the potential risks and benefits of HMOs, an overlooked tenure in housing research. </jats:sec