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Colorectal cancer (CRC) accounts for approximately 10% of all cancer cases worldwide. Conventional treatment has relied on chemotherapy, radiation therapy and surgery with limited success for patients with metastatic CRC. Toll like receptor (TLR) agonists have garnered attention for their ability to stimulate the innate immune system and consequently stimulate production of proinflammatory cytokines and activate an antitumor T cell response. However, activation of TLRs can also result in tumorigenesis and drug resistance depending on the specific TLR and cell that is targeted. Due to these contradictory effects of TLR stimulation, a key challenge is targeting specific cells, such as the dendritic cells or macrophages, to ensure the most optimal result. Additionally, TLR agonists are small molecules that can be cleared rapidly after local administration and can result in severe systemic side effects. This demonstrates the need to develop appropriate nanoparticle delivery systems for TLR agonists that can specifically target the innate immune system as a tool to treat CRC. In this review, the challenges in designing these nanoparticles will be discussed together with the recent advances of nanoparticle formulations containing TLR agonists.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by severe inflammation of the synovial tissue. Here, we assess the feasibility of liposome-loaded microbubbles as theranostic agents in a murine arthritis model. First, contrast-enhanced ultrasound (CEUS) was used to quantify neovascularization in this model since CEUS is well-established for RA diagnosis in humans. Next, the potential of liposome-loaded microbubbles and ultrasound (US) to selectively enhance liposome delivery to the synovium was evaluated with in vivo fluorescence imaging. This procedure is made very challenging by the presence of hard joints and by the limited lifetime of the microbubbles. The inflamed knee joints were exposed to therapeutic US after intravenous injection of liposome-loaded microbubbles. Loaded microbubbles were found to be quickly captured by the liver. This resulted in fast clearance of attached liposomes while free and long-circulating liposomes were able to accumulate over time in the inflamed joints. Our observations show that murine arthritis models are not well-suited for evaluating the potential of microbubble-mediated drug delivery in joints given: (i) restricted microbubble passage in murine synovial vasculature and (ii) limited control over the exact ultrasound conditions in situ given the much shorter length scale of the murine joints as compared to the therapeutic wavelength.

In juni 2020, bij het uitbreken van een kelder van een pand langs de Sint-Niklaasstraat als onderdeel van het grootschalige bouwproject De Meersen – De Looie, kwamen de laatste restanten van enkele graven aan het licht. De toevalsvondstprocedure werd in gang gezet en de zone kon, weliswaar in moeilijke omstandigheden en om die reden ook slechts in beperkte mate, onderzocht worden. De graven kunnen gekoppeld worden aan het laatmiddeleeuwse Noorderkerkhof van de Sint-Niklaaskerk, waarvan een groot deel in 2018 archeologisch onderzocht werd. De kenniswinst van deze toevalsvondst situeert zich enkel op het vlak van de ruimtelijke spreiding van het laatmiddeleeuwse kerkhof. Wel geeft deze toevalsvondst ook aan dat de oudste kerkhoflagen nog bewaard kunnen zijn onder de omliggende panden.

Bij infrastructuurwerken en het heraanleggen van het plein op de Oever te Antwerpen werden meerdere historische lagen gevuld met ceramiek en funderingen in baksteen aangetroffen. Tot dusver werd er van uitgegaan dat de rooilijn van de Oever "altijd" geweest zoals ze nu is. Nu bleek dat er op het plein zelf toch bebouwing aanwezig moet geweest zijn. Dat resulteert tot een hele andere opvatting over de ontwikkeling van het bouwblok. De lagen bevatten productie- en ovenafval afkomstig van een of meerdere pottenbakkers die gevestigd waren ten oosten van de site, langsheen de parallel gelegen Korte Ridderstraat. Op basis van de studie van het aardewerk zijn deze vullingspakketten te dateren tussen 1325 en 1375/1400. De muurrestanten zijn waarschijnlijk toe te schrijven aan een gebouw dat in de 16de eeuw op het plein de Oever stond en enkel zichtbaar en gekend is van een kaart uit 1585.

This Delphi study aims to reach a consensus in an international panel of bioethicists, fertility specialists, lawyers, academics, midwives/fertility nurses, psychologists and (former) egg donors about what information is relevant and what information is morally necessary for candidate egg donors in order to give a valid consent.

Through the history of rxisk.org, this article explores some of the Web’s effects on the production and circulation of pharmaceutical knowledge. RxISK is an independent website that solicits reports from patients in order to uncover drug-induced harms which clinical trials and national pharmacovigilance schemes fail to identify. The first part of the article locates the origins of the project in the nearly 15-year struggle to obtain recognition and redress for one particular side effect of selective serotonin reuptake inhibitor (SSRI) antidepressants—their ability to trigger violent or suicidal behavior. That struggle, I show, brought to light the ways in which modern evidence-making practices obscure the harms of pharmacological treatment. The second part, based on interviews with the site’s creators, examines how RxISK’s data collection practices seek to convert the Web from a site for the circulation of misinformation into a usable source of new knowledge about drugs. The project’s originality, I argue, lies in its effort to reframe the relation between anecdote and evidence so as to liberate the patient’s voice from the burden of representativeness. Within this reframed epistemology, the project is also freed from the imperative of large-scale data extraction that increasingly dominates the economy of digital health.

Een toevalsvondst van enkele menselijke beenderen die zich aankondigde als de intrigerende ontdekking van een mogelijk oorlogsslachtoffer uit WOI onder het terras van een woning langs de Maaldestedestraat in Zillebeke, bij Ieper, liep uiteindelijk op een sisser uit.

Dit hoofdstuk van de onderzoeksbalans is een eerste aanzet van een balans voor de archeologie van de Romeinse periode in Vlaanderen. Deze balans bestaat uit drie onderdelen. In een eerste onderdeel worden achtereenvolgens algemene inleidingen geschreven over de chronologische en ruimtelijke afbakeningen en indelingen, over het aantal bekende vindplaatsen en over het aantal gepubliceerde vindplaatsen en onderzoeken. In een tweede onderdeel wordt per bronnencategorie ingeschat wat aan gegevens beschikbaar is. Daarbij is ook enige aandacht besteed aan de niet-archeologische bronnen (literaire, epigrafische en numismatische). In een derde onderdeel overlopen we de stand van onze kennis met betrekking tot de diverse aspecten van de provinciaal-Romeinse samenleving, zoals die a.h.v. de bronnen bestudeerd kunnen worden.

Listeria monocytogenesis a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine againstListeriais available. AttenuatedListeriastrains offer protection and are tested as antitumor vaccine vectors, but would benefit from a better knowledge on immunodominant vector antigens. To identify novel antigens, we screened forListeriaepitopes presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detected 68Listeriaepitopes from 42 different bacterial proteins, including several known antigens. Peptide epitopes presented on different cell lines were often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations resulted in specific CD8+ T-cell responses and high levels of protection in vaccination challenge experiments in mice. Our results pave the way for the development of a clinical mRNA vaccine againstListeriaand aid to improve attenuatedListeriavaccines and vectors, demonstrating the power of immunopeptidomics for next-generation bacterial vaccine development.

Op de storthoop met aarde afkomstig van rioleringswerken (bouwheer gemeente Asse) vond men fragmenten van menselijk botmateriaal. Deze grond was afkomstig van de zone ten noorden van de kerk van Mollem. Naar aanleiding van deze melding via het digitaal meldingsformulier op 21-03-2018 inspecteerde archeoloog Kristine Magerman (Agilas vzw) dezelfde avond de rioleringssleuf. Zij trof ter plaatse menselijk botmateriaal aan in het zuidelijk profiel van de sleuf. De sleuf was op dat moment ongeveer één meter opnieuw opgevuld door de aannemer. Op basis van de melding en haar verslag besloot het agentschap Onroerend Erfgoed om een terreinbezoek te doen op 22-03-2018. Naar aanleiding van dit bezoek besliste Katrien Cousserier dat een terreinonderzoek noodzakelijk was. Dit terreinonderzoek vond plaats op 26-03-2018 en werd uitgevoerd door Katrien Cousserier en Marijn Van Gils. Het terreinwerk kon dezelfde dag afgerond worden. De uitgewerkte resultaten van dit archeologisch onderzoek, de verdere verwerking van de onderzoeksgegevens en vondsten, en de interpretatie van de site binnen de ruimere historische context vormen het onderwerp van dit eindverslag.

Lawyers in the ongoing opioid litigation have obtained millions of documents from the drug manufacturers, distributors, and pharmacies blamed for the ravages of the opioid crisis. What will...

Inflammasomes are multi-protein complexes that guard against cellular stress and microbial infections. Inflammasome activation studies frequently require delivery of pathogen-derived virulence factors into the cytosol of macrophages and other innate immune cells. This is a challenging requirement since primary macrophages are difficult-to-transfect, especially when it comes to the intracellular delivery of proteins. Here, we report on the use of nanoparticle-sensitized photoporation as a promising upcoming intracellular delivery technology for delivering proteins of various molecular weights into the cytosol of primary macrophages. While 60-70 nm gold nanoparticles are the most commonly used sensitizing nanoparticles for photoporation, here we find that 0.5 μm iron oxide nanoparticles perform markedly better on primary macrophages. We demonstrate that LFn-FlaA or lipopolysaccharides can be delivered in primary macrophages resulting in activation of the NLRC4 or the non-canonical inflammasome, respectively. We furthermore show that photoporation can be used for targeted delivery of these toxins into selected cells, opening up the possibility to study the interaction between inflammasome activated cells and surrounding healthy cells. Taken together, these results show that nanoparticle-sensitized photoporation is very well suited to deliver pathogenic virulence factors in primary macrophages, thus constituting an effective new enabling technology for inflammasome activation studies.

De Vlaamse Regering vraagt aan het agentschap Onroerend Erfgoed elk jaar een rapport waarin wat betreft archeologie o.a. volgende elementen aan bod komen: • een overzicht van het aantal vooronderzoeken en opgravingen alsook de duur ervan, • een overzicht van de resultaten van deze onderzoeken, • een overzicht van de voorgestelde en goedgekeurde maatregelen uit de archeologienota’s, • de financiële implicaties van het archeologisch onderzoek en de werking van het archeologisch solidariteitsfonds. Dit rapport biedt een antwoord op de tweede vraag1 en wordt als apart onderzoeksrapport aangeboden op de open archives repository (OAR) van het agentschap Onroerend Erfgoed. De andere vragen worden beantwoord in het rapport ‘Evaluatie archeologie 2021. Uitvoering archeologieregelgeving. In wat volgt, worden de resultaten samengevat van de archeologische projecten die onder de regelgeving van het Onroerenderfgoeddecreet vielen, en waarvoor tussen 1 januari en 31 december 2021 eindverslagen en nota’s met eindafwerking in het archeologieportaal3 opgeladen zijn. Sinds dit jaar worden hieraan ook de eindverslagen van het syntheseonderzoek4 toegevoegd.

Op 9 maart 2018 werden tijdens graafwerken op een braakliggend terrein tussen de Hofstraat en de Kastenjedreef te Elewijt voor een nieuwbouwwoning Romeinse scherven aangetroffen en gemeld als toevalsvondst. In de periode van 19 maart-6 april 2018 voerde het agentschap Onroerend Erfgoed opgravingen uit over een oppervlakte van 1950 m², in de noordelijke periferie van de vicus van Elewijt. De Romeinse weg die van de vicus in noordelijke richting naar Rumst voerde en in zuidelijke richting naar Baudecet, doorkruist het opgravingsterrein. Haaks op deze weg liep een onverharde weg, waarvan we 3 verschillende wegggreppels hebben teruggevonden. Het is niet duidelijk welke bestemmingen deze weg had. In de eerste eeuw was de vicus op deze plaats ingedeeld door een aantal perceelsgreppels waarvan er slechts enkele bewaard zijn. Op het einde van de eerste eeuw of het begin van de 2de eeuw ontwikkelt zich ten oosten van de weg naar Rumst een ambachtelijke zone met oventjes voor metaalbewerking. Deze ambachtelijke zone blijft in gebruik tot het begin van de 3de eeuw. Een bijzondere vondst is een depositie van vaatwerk in koperlegering in de noordoostelijke zone van het opgravingsareaal.

Listeria monocytogenesis a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine againstListeriais available. AttenuatedListeriastrains offer protection and are tested as antitumor vaccine vectors, but would benefit from a better knowledge on immunodominant vector antigens. To identify novel antigens, we screen forListeriapeptides presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detect 68Listeriaimmunopeptides from 42 different bacterial proteins, including several known antigens. Peptides presented on different cell lines are often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations results in specific CD8+ T-cell responses and induces protection in vaccination challenge experiments in mice. Our results can serve as a starting point for the development of a clinical mRNA vaccine againstListeriaand aid to improve attenuatedListeriavaccines and vectors, demonstrating the power of immunopeptidomics for next-generation bacterial vaccine development.

Op 15 november 2019 werden bij graafwerken voor de fundering voor een nieuw appartementsgebouw verscheidene kuilen aangetroffen. Na evaluatie ter plaatse werd beslist om de sporen te registreren. Er werd in totaal ca. 650 m2 onderzocht. In dit eindverslag worden de aangesneden sporen op de onderzochte percelen besproken en toegelicht alsook de archeologische en historische voorkennis van dit deel van de gemeente. De resultaten van de studie van de verschillende vondstencategorieën zijn eveneens in dit verslag opgenomen.

Ultrasound-triggered drug-loaded microbubbles have great potential for drug delivery due to their ability to locally release drugs and simultaneously enhance their delivery into the target tissue. We have recently shown that upon applying ultrasound, nanoparticle-loaded microbubbles can deposit nanoparticles onto cells grown in 2D monolayers, through a process that we termed "sonoprinting". However, the rigid surfaces on which cell monolayers are typically growing might be a source of acoustic reflections and aspherical microbubble oscillations, which can influence microbubble-cell interactions. In the present study, we aim to reveal whether sonoprinting can also occur in more complex and physiologically relevant tissues, by using free-floating 3D tumor spheroids as a tissue model. We show that both monospheroids (consisting of tumor cells alone) and cospheroids (consisting of tumor cells and fibroblasts, which produce an extracellular matrix) can be sonoprinted. Using doxorubicin-liposome-loaded microbubbles, we show that sonoprinting allows to deposit large amounts of doxorubicin-containing liposomes to the outer cell layers of the spheroids, followed by doxorubicin release into the deeper layers of the spheroids, resulting in a significant reduction in cell viability. Sonoprinting may become an attractive approach to deposit drug patches at the surface of tissues, thereby promoting the delivery of drugs into target tissues. ispartof: Journal Of Controlled Release vol:316 pages:79-92 ispartof: location:Netherlands status: published

Summary The fungus Aspergillus fumigatus is ubiquitous in nature and the most common cause of invasive pulmonary aspergillosis (IPA) in patients with a compromised immune system. The development of IPA in patients under immunosuppressive treatment or in patients with primary immunodeficiency demonstrates the importance of the host immune response in controlling aspergillosis. However, study of the host-microbe interaction has been hampered by the lack of tools for their non-invasive assessment. We developed a methodology to study the response of the host's immune system against IPA longitudinally in vivo by using fluorine-19 magnetic resonance imaging (19F MRI). We showed the advantage of a perfluorocarbon-based contrast agent for the in vivo labeling of macrophages and dendritic cells, permitting quantification of pulmonary inflammation in different murine IPA models. Our findings reveal the potential of 19F MRI for the assessment of rapid kinetics of innate immune response against IPA and the permissive niche generated through immunosuppression., Graphical Abstract, Highlights • Host-pathogen immune response is visualized in vivo and quantified against IPA • Modified PFC-based nanoparticles were used for in vivo labeling of immune cells • Clinical immunosuppression depict dynamic immune response upon fungal challenge • 19F MRI showed follow-up of labeled immune cells in individual animals over time, Infection Control in Health Technology; Medical Imaging; Mycology

In the last couple of decades, ultrasound-driven microbubbles have proven excellent candidates for local drug delivery applications. Besides being useful drug carriers, microbubbles have demonstrated the ability to enhance cell and tissue permeability and, as a consequence, drug uptake herein. Notwithstanding the large amount of evidence for their therapeutic efficacy, open issues remain. Because of the vast number of ultrasound- and microbubble-related parameters that can be altered and the variability in different models, the translation from basic research to (pre)clinical studies has been hindered. This review aims at connecting the knowledge gained from fundamental microbubble studies to the therapeutic efficacy seen in in vitro and in vivo studies, with an emphasis on a better understanding of the response of a microbubble upon exposure to ultrasound and its interaction with cells and tissues. More specifically, we address the acoustic settings and microbubble-related parameters (i.e., bubble size and physicochemistry of the bubble shell) that play a key role in microbubble cell interactions and in the associated therapeutic outcome. Additionally, new techniques that may provide additional control over the treatment, such as monodisperse microbubble formulations, tunable ultrasound scanners, and cavitation detection techniques, are discussed. An in-depth understanding of the aspects presented in this work could eventually lead the way to more efficient and tailored microbubble-assisted ultrasound therapy in the future.

Tracking the autoreactive T-cell migration in the pancreatic region after labeling with fluorinated nanoparticles (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio)propionate]-perfluoro-15-crown-5-ether nanoparticles, PDP-PFCE NPs) in a diabetic murine model using 19F MRI. Synthesis of novel PDP-PFCE fluorine tracer was performed for in vitro labeling of T cells. Labeling conditions were optimized using different PDP-PFCE NPs concentrations. For in vivo 19F MRI, mice were longitudinally followed after adoptive transfer of activated, autoreactive, labeled T cells in NOD.SCID mice. Established MR protocols were used for challenging T cell labeling to track inflammation in a model of diabetes after successful labeling of CD4+ and CD8+ T cells with PDP-PFCE NPs. However, T cells were difficult to be detected in vivo after their engraftment in animals. We showed successful in vitro labeling of T cells using novel fluorinated liposomal nanoparticles. However, insufficient and slow accumulation of labeled T cells and subsequent T cell proliferation in the pancreatic region remains as limitations of in vivo cell imaging by 19F MRI.

For all their concern with the nature of medical authority, historians of medicine have paid remarkably little attention to the history of the medical script, the main medium in and through which the doctor’s authority is enacted. This essay analyzes the medical prescription as an instance of a written performative. While focusing on the changing uses of one particular documentary genre in turn-of-the-twentieth-century France, it seeks to outline a broader theory of graphic performativity, or of the conditions under which the symbolic power of the oral performance is transferred and transformed as it is transcribed on paper.

De Vlaamse Regering vraagt aan het agentschap Onroerend Erfgoed elk jaar een rapport waarin wat betreft archeologie o.a. volgende elementen aan bod komen (in navolging van het Onroerenderfgoeddecreet, artikel 5.6.1, §2: •een overzicht van het aantal vooronderzoeken en opgravingen alsook de duur ervan •een overzicht van de resultaten van deze onderzoeken •een overzicht van de voorgestelde en goedgekeurde maatregelen uit de archeologienota’s •de financiële implicaties van het archeologisch onderzoek en de werking van het archeologischsolidariteitsfonds. Dit rapport biedt een antwoord op de tweede vraag.

Tijdens graafwerken voor een nieuwe wadi, in het westelijk deel van het Domein Rivierenhof te Antwerpen, net ten zuiden van een sportlokaal werden meerdere kuilen aangetroffen gevuld met talrijke dierenbeenderen, ceramiek, glas en metaalslakken. In totaal werden 13 kuilen opgegraven, gelegen op twee parallelle rijen. De westelijke rij bestaat uit zeven min of meer rechthoekige, op regelmatige afstand liggende kuilen (sporen S1 tot S7). Deze kuilen bevatten een grote hoeveelheid dierenbeenderen, huishoudelijke ceramiek en glas, en wat metalen voorwerpen. De oostelijke rij bestaat uit zes cirkelvormige, op regelmatige afstand liggende kuilen (sporen S8 tot S13). Bij de meeste bevat de vulling grote metaalslakken terwijl dierenbeenderen, huishoudelijke ceramiek en glas vrijwel ontbreken. Wel werd in deze sporen frequent industrieel aardewerk gevonden.

Het archeologisch onderzoek leverde gegevens op uit een groot aantal archeologische periodes, gaande van het middenpaleolithicum tot de nieuwe tijden, met enkele belangrijke inzichten: een bijna continue aanwezigheid in het opgravingsareaal in de steentijden, met enkele duidelijke concentraties uit het finaalpaleolithicum/vroegmesolithicum, en helaas minder ‘grijpbare’ en meer diffuse gegevens voor de andere periodes. Wellicht was het gebied in met name het middenneolithicum eerder gelegen in de periferie van sites dichter tegen de loop van de vroegere Schelde, bv. op de plaats van de ‘Paardenweide’. Ook uit de vroege ijzertijd en Romeinse periode werden aanwijzingen voor bewoning aangetroffen, in beide gevallen werd wellicht een gedeelte van een erf aangesneden in zone B. Uit de vroege en volle middeleeuwen zijn de archeologische gegevens heel schaars, maar in de laatmiddeleeuwse periode werd in zone A een feodale motteversterking opgericht, die samen met de vroegere kerk, ongeveer 300 m ten zuidoosten, ongetwijfeld de kern vormde van het laatmiddeleeuwse Wichelen. Met name het aardewerk duidt op een bewoning van deze site in de 13de en 14de eeuw. Ten slotte wijzen de gegevens op verschillende fasen van inrichting van zone B van de 15de tot de 18de eeuw, vanaf de 17de eeuw, wellicht gerelateerd aan het historisch gekende Hof te Zijpen. Zoals diverse andere onderzoeken in de Sigma-gebieden wijzen deze opgravingsgegevens opnieuw op het belang van de alluviale gebieden voor de archeologie van de diverse periodes, vanaf de steentijd.

Tijdens grond- en infrastructuurwerken, op het domein van het kasteel van Kwabeek, het huidige stadhuis van de gemeente Boutersem, trof men robuust muurwerk aan in bak- en Gobertangesteen. Bij de evaluatie van de toevalsvondst op het terrein bleek al gauw dat het hier ging om restanten van een belangrijke historische site en de funderingen van voorlopers en verbouwingen van het huidige kasteel met zijn aansluitende slotgracht. Dit eindverslag bevat de resultaten het onderzoek van de aanwezige sporen van het oude kasteel van Kwabeek die vooral uit muurrestanten bestonden. Aangezien het aantal archeologische aardewerk-, glas- en metaalvondsten, het aantal botfragmenten en het aantal genomen bodemmonsters voor macrobotanisch onderzoek beperkt waren, was een assessment niet relevant en worden alle vondsten in dit eindverslag behandeld.

Het onderzochte perceel bevindt zich in de Tongersveldstraat 4 te Tongeren. Dit terrein ligt aan de noordwestelijke randzone van het zuidwest-grafveld van de Romeinse stad Atuatuca Tungrorum. In dit eindverslag worden de onderzochte profielen en aangesneden Romeinse structuren uit 2017 toegelicht. Ook de structuur van de toevalsvondst uit 2018 wordt bij de interpretatie van de site betrokken. De verdere verwerking van de onderzoeksgegevens en vondsten worden besproken en geanalyseerd binnen de ruimere historische en archeologische context van de Romeinse hoofdstad van de civitas Tungrorum.

mRNA therapeutics have become the focus of molecular medicine research. Various mRNA applications have reached major milestones at high speed in the immuno-oncology field. This can be attributed to the knowledge that mRNA is one of nature’s core building blocks carrying important information and can be considered as a powerful vector for delivery of therapeutic proteins to the patient.For a long time, the major focus in the use of in vitro transcribed mRNA was on development of cancer vaccines, using mRNA encoding tumor antigens to modify dendritic cells ex vivo. However, the versatility of mRNA and its many advantages have paved the path beyond this application. In addition, due to smart design of both the structural properties of the mRNA molecule as well as pharmaceutical formulations that improve its in vivo stability and selective targeting, the therapeutic potential of mRNA can be considered as endless.As a consequence, many novel immunotherapeutic strategies focus on the use of mRNA beyond its use as the source of tumor antigens. This review aims to summarize the state-of-the-art on these applications and to provide a rationale for their clinical application.

Introduction Dendritic cells (DCs) and macrophages, two important antigen presenting cells (APCs) of the innate immune system, are being explored for the use in cell-based cancer immunotherapy. For this application, the therapeutic potential of patient-derived APCs is increased by delivering different types of functional macromolecules, such as mRNA and pDNA, into their cytosol. Compared to the use of viral and non-viral delivery vectors, physical intracellular delivery techniques are known to be more straightforward, more controllable, faster and generate high delivery efficiencies. Areas covered This review starts with electroporation as the most traditional physical transfection method, before continuing with the more recent technologies such as sonoporation, nanowires and microfluidic cell squeezing. A description is provided of each of those intracellular delivery technologies with their strengths and weaknesses, especially paying attention to delivery efficiency and safety profile. Expert opinion Given the common use of electroporation for the production of therapeutic APCs, it is recommended that more detailed studies are performed on the effect of electroporation on APC fitness, even down to the genetic level. Newer intracellular delivery technologies seem to have less impact on APC functionality but further work is needed to fully uncover their suitability to transfect APCs with different types of macromolecules.

Graphical abstract, The recent approval of messenger RNA (mRNA)-based vaccines to combat the SARS-CoV-2 pandemic highlights the potential of both conventional mRNA and self-amplifying mRNA (saRNA) as a flexible immunotherapy platform to treat infectious diseases. Besides the antigen it encodes, mRNA itself has an immune-stimulating activity that can contribute to vaccine efficacy. This self-adjuvant effect, however, will interfere with mRNA translation and may influence the desired therapeutic outcome. To further exploit its potential as a versatile therapeutic platform, it will be crucial to control mRNA’s innate immune-stimulating properties. In this regard, we describe the mechanisms behind the innate immune recognition of mRNA and provide an extensive overview of strategies to control its innate immune-stimulating activity. These strategies range from modifications to the mRNA backbone itself, optimization of production and purification processes to the combination with innate immune inhibitors. Furthermore, we discuss the delicate balance of the self-adjuvant effect in mRNA vaccination strategies, which can be both beneficial and detrimental to the therapeutic outcome.

International audience; In ultrasound-mediated drug delivery, bubbles decorated with a functional payload are convenient transport vehicles and offer highly localized release. These bubbles are traceable using ultrasound, can be activated on demand and protect their cargo from the natural clearing mechanisms of the body. In addition, microbubbles offer an active way to mechanically overcome biological barriers. Such microbubbles are therefore being extensively investigated for single cell, gene and cancer therapy. Experimental investigation of microbubble interactions with cell monolayers has led to the description of a phenomenon termed ?sonoprinting?: confocal imaging shows how exposure of the microbubbles to ultrasound can result in the deposition of their payload in patches onto the cell membrane. In parallel, investigation of single microbubbles with a combination of ultra-high-speed imaging at 10 million frames per second, and high-speed fluorescence imaging at 50,000 frames per second demonstrates how non-spherical bubble oscillations induce both, the release of the drug payload and its transport by microbubble-induced streaming. These observations are validated with a simple theoretical model based on the Rayleigh-Plesset equation. In order to reconcile these observations, we combine three optical imaging techniques to capture the bubble-cell interactions on timescales ranging from sub-microseconds to several seconds. We observe that non-spherically oscillating microbubbles release their nanoparticle payload in the first few ultrasound cycles. At low pressures, the released nanoparticles are transported away by microstreaming, as observed for single microbubbles. This configuration, however, does not favor of the nanoparticles uptake. Higher pressures (> 300 kPa) and longer ultrasound pulses (>100 cycles) lead to rapid translation of the microbubbles and transport of the released nanoparticles in the microbubbles wake, eventually leading to the deposition of nanoparticles in elongated patches onto the cell membrane.

Onderzoeksbalans archeologie in Vlaanderen Versie 1, 11/12/2008: Natuurwetenschappelijk onderzoek en dateringen

Middeleeuwse en postmiddeleeuwse sporen aan de Markt te Asse (Vlaams-Brabant) Eindverslag van een toevalsvondst

The pathogenesis of type 1 diabetes (T1D) involves presentation of islet-specific self-antigens by dendritic cells (DCs) to autoreactive T cells, resulting in the destruction of insulin-producing pancreatic beta cells. We aimed to study the dynamic homing of diabetes-prone DCs to the pancreas and nearby organs with and without induction of pancreatic stress in a T1D susceptible model of repeated streptozotocin (STZ) injection.In vitro labeling of activated bone marrow-derived DCs (BMDCs) from NOD (Nonobese diabetes) mice was performed using zonyl perfluoro-15-crown-5-ether nanoparticles (ZPFCE-NPs). Internalization of particles was confirmed by confocal microscopy. Two groups of NOD.SCID (nonobese diabetic/severe combined immunodeficiency) mice with (induced by low dose STZ administration) or without pancreatic stress were compared. Diabetogenic BMDCs loaded with BDC2.5 mimotope were pre-labeled with ZPFCE-NPs and adoptively transferred into mice. Longitudinal in vivo fluorine MRI (In vitro flow cytometry and confocal microscopy confirmed high uptake of nanoparticles in BMDCs during the process of maturation. Migration/homing of activated and ZPFCE-NP- labeled BMDCs to different organs was monitored and quantified longitudinally, showing highest cell density in pancreas at 48-h time-point. Based onWe showed the potential of

As part of the study of the early medieval cemetery at Broechem (Belgium), human bones from 32 cremation graves have been dated through radiocarbon (14C) analysis. It was noted that many of the dates were not in accordance with the chronological ranges provided by the characteristics of the cultural artifacts deposited in the graves. In fact, the human bones were “older” than the artifacts. Subsequently, a number of animal bones (in all cases from domestic pigs) was radiocarbon dated, yielding dates that were more consistent with the information from the cultural artifacts than the human bones. The dates obtained on human and pig bones from the same grave often differed around 100 radiocarbon years. This paper tries to find an explanation for the pattern observed, concentrating on two hypotheses: aquatic reservoir versus old wood effects. The evaluation takes into account additional radiocarbon dates derived from charcoal fragments of the funeral pyre, from both short-lived and long-lived taxa. A conclusive explanation for the anomalous radiocarbon dates could not be reached but clear suggestions can be put forward for future experimental work that will without doubt shed more light upon the interpretational problems raised.

To date, mRNA-based biologics have mainly been developed for prophylactic and therapeutic vaccination to combat infectious diseases or cancer. In the past years, optimization of the characteristics of in vitro transcribed mRNA has led to significant reduction of the inflammatory responses. Thanks to this, mRNA therapeutics have entered the field of passive immunization. Here, we established an mRNA treatment that is based on mRNA that codes for a bispecific single-domain antibody construct that can selectively recruit innate immune cells to cells infected with influenza A virus. The constructs consist of a single-domain antibody that binds to the ectodomain of the conserved influenza A matrix protein 2, while the other single-domain antibody binds to the activating mouse Fcγ receptor IV. Formulating the mRNA into DOTAP (1,2-dioleoyl-3-trimethylammonium-propane)/cholesterol nanoparticles and delivering these intratracheally to mice allowed the production of the bispecific single-domain antibody in the lungs, and administration of these mRNA-particles prior to influenza A virus infection was associated with a significant reduction in viral titers and a reduced morbidity in mice. Overall, our data provide evidence that the local delivery of mRNA encoding a bispecific single-domain antibody format in the lungs could be a promising pulmonary antiviral prophylactic treatment., Graphical Abstract, We present a prophylactic intervention that is based on mRNA that codes for a bispecific single-domain antibody construct that selectively recruits innate immune cells to cells infected with influenza A virus. Intratracheal delivery of this mRNA construct could lower mortality and morbidity of influenza A virus challenged mice.

ispartof: Relicta. Archeologie, Monumenten- en Landschapsonderzoek in Vlaanderen vol:18 pages:269-269 status: published

Therapeutic ultrasound strategies that harness the mechanical activity of cavitation nuclei for beneficial tissue bio-effects are actively under development. The mechanical oscillations of circulating microbubbles, the most widely investigated cavitation nuclei, which may also encapsulate or shield a therapeutic agent in the bloodstream, trigger and promote localized uptake. Oscillating microbubbles can create stresses either on nearby tissue or in surrounding fluid to enhance drug penetration and efficacy in the brain, spinal cord, vasculature, immune system, biofilm or tumors. This review summarizes recent investigations that have elucidated interactions of ultrasound and cavitation nuclei with cells, the treatment of tumors, immunotherapy, the blood-brain and blood-spinal cord barriers, sonothrombolysis, cardiovascular drug delivery and sonobactericide. In particular, an overview of salient ultrasound features, drug delivery vehicles, therapeutic transport routes and pre-clinical and clinical studies is provided. Successful implementation of ultrasound and cavitation nuclei-mediated drug delivery has the potential to change the way drugs are administered systemically, resulting in more effective therapeutics and less-invasive treatments. (E-mail: k.kooiman@erasmusmc.nl) (C) 2020 The Author(s). Published by Elsevier Inc. on behalf of World Federation for Ultrasound in Medicine & Biology.

PurposeTransplantation of pancreatic islets (PIs) is a promising therapeutic approach for type 1 diabetes. The main obstacle for this strategy is that the outcome of islet engraftment depends on the engraftment site. It was our aim to develop a strategy for using non-invasive imaging techniques to assess the location and fate of transplanted PIs longitudinally in vivo.ProceduresIn order to overcome the limitations of individual imaging techniques and cross-validate findings by different modalities, we have combined fluorine magnetic resonance imaging (F-19 MRI), fluorescence imaging (FLI), and bioluminescent imaging (BLI) for studying subcutaneously transplanted PIs and beta cell-like cells (INS-1E cell line) in vivo. We optimized the transduction (using lentiviral vectors) and labeling procedures (using perfluoro crown ether nanoparticles with a fluorescence dye) for PIs and INS-1E cell imaging.ResultsThe feasibility of using the proposed imaging methods for PI assessment was demonstrated both in vitro and in vivo. Our data suggested that F-19 MRI is suitable for high-resolution localization of transplanted cells and PIs; FLI is essential for confirmation of contrast localization by histology; and BLI is a reliable method to assess cell viability and survival after transplantation. No significant side effects on cell viability and function have been observed.ConclusionsThe proposed tri-modal imaging platform is a valuable approach for the assessment of engrafted PIs in vivo. It is potentially suitable for comparing different transplantation sites and evaluating novel strategies for improving PI transplantation technique in the future.