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    Diagnostic profiling of MDSCs in sepsis

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    With 50 million cases and 11 million deaths per year, sepsis is one of the leading causes of death worldwide. Sepsis is caused by a dysregulated host response to an infection, which consists of concurrent inflammatory and immunosuppressive reactions. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells characterized by their immunosuppressive properties, rising in inflammatory diseases. MDSCs are subdivided into polymorphonuclear MDSCs (PMN-MDSCs) and monocytic MDSCs (M-MDSCs) based on their relationship with mature PMNs and monocytes. It is unknown how their level varies over time in human sepsis. We hypothesized that MDSCs have diagnostic and prognostic potential in sepsis patients. In this thesis, we aimed to illustrate the dynamic profile of MDSCs in critically ill patients in relation to sepsis severity, secondary infections, and mortality. Four study cohorts were used: 1) healthy subjects infused with endotoxin, 2) non-infectious, critically ill patients without antibiotic therapy (PIPOVAP study), 3) hospitalized coronavirus 2019 (COVID-19) patients and, 4) sepsis patients with multi-organ dysfunction syndrome (MODS) (INCLASS study). Serial samples of peripheral blood were used to quantify MDSCs by flow cytometry and FlowSOM to avoid gating biases. M-MDSCs were defined as HLA-DRlow monocytes, and PMN-MDSCs as CD16low granulocytes. Furthermore, we quantified up to 49 cytokines by multiplex bead assay, and analysed the functionality of monocytes and dendritic cells (DCs) in ex vivo stimulated whole blood by intracellular cytokine staining and flow cytometry. Endotoxin infusion in healthy subjects induced a quick, massive, and transient accumulation of MDSCs in peripheral blood. PMN-MDSCs increased 40-fold to reach up to 43% of all granulocytes 6-8 hours after infusion. M-MDSCs increased 10-fold 8 hours after endotoxin infusion comprising more than half of total monocytes. After 24 hours, PMN-MDSCs and M-MDSCs returned to baseline levels. In patients enrolled in the PIPOVAP, COVID-19, and INCLASS studies, the blood concentration of PMN-MDSCs and M-MDSCs were high at study inclusion and correlated to disease severity. In the PIPOVAP study, high levels of M-MDSCs also correlated to the development of secondary gram-negative infections. High MDSCs were associated with mortality in non-infectious critically ill patients (PIPOVAP), but with survival in sepsis patients with MODS (INCLASS). MDSCs correlated with the concentrations of blood cytokines, chemokines, and growth factors in the PIPOVAP and COVID-19 studies. Finally, 3 months after the COVID-19 diagnosis, irrespective of initial disease severity, MDSCs were back to normal levels whilst the production of cytokines by blood cells was still largely affected. Altogether, we report that MDSCs quickly rise during endotoxemia and are associated with sepsis severity. Thus, MDSCs might represent valuable tools to screen vulnerable patients in the intensive care. Additionally, we show for the first time that a high level of MDSCs is associated with improved outcomes in a subset of extremely ill sepsis patients with MODS. Overall, MDSCs may represent sepsis biomarkers and targets of therapy. To pursue clinical development, the quantification method of MDSCs in patients need to be standardized, and the function and plasticity of MDSCs during sepsis should be further explored. -- Avec 50 millions de cas et 11 millions de dĂ©cĂšs par an, le sepsis est l'une des principales causes de dĂ©cĂšs dans le monde. Le sepsis est causĂ© par une rĂ©ponse dĂ©rĂ©gulĂ©e de l'hĂŽte en rĂ©ponse Ă  une infection, qui consiste en des rĂ©actions inflammatoires et immunosuppressives concomitantes. Les cellules suppressives d'origine myĂ©loĂŻde (MDSCs) sont des cellules myĂ©loĂŻdes immatures caractĂ©risĂ©es par leurs propriĂ©tĂ©s immunosuppressives. Les MDSCs sont subdivisĂ©es en MDSCs polymorphonuclĂ©aires (PMN- MDSCs) et MDSCs monocytaires (M-MDSCs) en fonction de leur relation avec les PMNs et monocytes matures. L’évolution des MDSCs au cours d’un sepsis humain est trĂšs peu documentĂ©e. Pour combler cette lacune, dans cette thĂšse nous avons analysĂ© l’expression des MDSCs dans le sang en regard de la sĂ©vĂ©ritĂ© du sepsis et de paramĂštres immunologiques. Quatre Ă©tudes de cohortes ont Ă©tĂ© utilisĂ©es: 1) des sujets sains perfusĂ©s avec de l'endotoxine, un composant de bactĂ©ries gram-nĂ©gatives qui permet de mimer une infection bactĂ©rienne (Ă©tude endotoxin), 2) des patients non infectieux, hospitalisĂ©s aux soins intensifs (SI) (Ă©tude PIPOVAP), 3) des patients coronavirus 2019 hospitalisĂ©s (Ă©tude COVID-19) et 4) des patients sepsis prĂ©sentant un syndrome de dĂ©faillance multiviscĂ©rale associĂ© Ă  une mortalitĂ© d’environ ~70% (Ă©tude INCLASS). Des Ă©chantillons sĂ©riels de sang pĂ©riphĂ©rique ont Ă©tĂ© collectĂ©s pour quantifier les MDSCs. En outre, nous avons mesurĂ© une cinquantaine de cytokines, chimiokines et facteurs de croissances et analysĂ© la fonctionnalitĂ© des globules blancs du sang complet. La perfusion d'endotoxine chez des sujets sains induisait une accumulation rapide, massive (pouvant aller jusqu’à 30-40% de tous les globules blancs) et transitoire de MDSCs. AprĂšs 24 heures, les MDSCs Ă©taient revenus Ă  un taux normal. Les MDSCs Ă©taient Ă©levĂ©es chez les patients inclus dans les Ă©tudes PIPOVAP, COVID-19 et INCLASS. Cette augmentation corrĂ©lait avec la gravitĂ© de la maladie et, dans l'Ă©tude PIPOVAP, avec le dĂ©veloppement d'infections nosocomiales. Des taux Ă©levĂ©s de MDSCs Ă©taient associĂ©s Ă  la mortalitĂ© chez les patients non-infectieux hospitalisĂ©s aux SI. Par contre, une accumulation de MDSCs Ă©tait associĂ©e Ă  un devenir favorable chez les patients sepsis ayant dĂ©veloppĂ© un syndrome de dĂ©faillance multiviscĂ©rale. Finalement, chez les patients COVID-19 rĂ©-analysĂ©s 3 mois aprĂšs leur hospitalisation, les MDSCs Ă©taient normales alors que certains dysfonctionnements immunitaires Ă©taient dĂ©tectĂ©s. Ceux-ci qui pourraient ĂȘtre associĂ©s au syndrome de « COVID long ». En rĂ©sumĂ©, nous rapportons que les MDSCs augmentent rapidement et fortement dans le sang d’individus exposĂ©s Ă  un composant de bactĂ©rie, et qu’elles sont associĂ©es Ă  la sĂ©vĂ©ritĂ© du sepsis. Ainsi, les MDSCs ont un potentiel diagnostique et pronostique chez les patients atteints de sepsis. Par ailleurs, les MDSCs pourraient reprĂ©senter des cibles d’immunothĂ©rapie, d’autant plus que des traitements ciblant les MDSCs sont actuellement testĂ©es dans le cadre de cancers. -- The immune system protects the human body against infections caused by microorganisms, like viruses and bacteria. White blood cells are one important part of the immune system. White blood cells kill invading organisms as well as warn and activate other white blood cells to increase host defences. However, sometimes the immune system does not respond appropriately to an infection, or it cannot control it. When that happens, white blood cells injure tissues through collateral damage while trying to contain the infection. This can lead to organ failure, which is associated with a high mortality rate. When this happens, it is called sepsis. With 50 million cases and 11 million deaths per year, sepsis is a global health priority. During sepsis, white blood cells can respond too strongly, stop functioning, or even repress the function of other cells. This is called immunosuppression. Immunosuppression can cause long-term effects in recovered sepsis patients, such as the development of new infections and heart diseases. In this thesis, we were interested in a particular type of white blood cells called myeloid-derived suppressor cells (MDSCs). MDSCs restrict the function of other white blood cells. In short, they are immunosuppressive. Healthy people have very few MDSCs, but patients with inflammatory diseases such as cancer, have high levels of MDSCs. How fast MDSCs respond after an infection, and what type of impact these cells have during sepsis are largely unknown. We aimed to give an in-depth view of the dynamics of MDSCs in conditions of inflammation and infection. We set up four studies to address our aim. Blood was collected from individuals at different time intervals to measure MDSCs and other immune parameters. The first study was with healthy volunteers who were injected with bacterial compounds, which trigger white blood cells mimicking bacterial sepsis. We observed that MDSC levels rise strongly 2 hours after infusion and remained high until 8 hours after the injection. MDSCs returned to normal levels after 24 hours. This tells us that MDSCs are very fast responders when the host is triggered by a bacterial compound. In the second study, we tested critically ill patients in the Intensive Care Unit (ICU) without an infection. We noticed that patients with high levels of MDSCs were more likely to become infected and to die. We assume that MDSCs suppressed the function of anti-microbial white blood cells, increasing the risks of infection. In the third study, we looked at COVID-19 patients. COVID-19 patients can develop sepsis, which is one of the reasons why some must be hospitalized. Patients admitted to the ICU had more MDSCs than patients who did not require admission to the ICU. In the fourth study, we analysed severe sepsis patients with multiple organ dysfunctions. Patients with high levels of MDSCs were more likely to survive. Most likely, MDSCs were beneficial in these severe patients because MDSCs were counterbalancing the otherwhite blood cells that were overreacting and damaging. To conclude, this thesis shows 1) how MDSCs are modulated during sepsis, and 2) that MDSCs can be helpful or hurtful depending on the degree of sepsis severity. We propose to use MDSCs as signals of sepsis severity, and possibly as targets of therapy as currently tested in cancer patients. -- Le systĂšme immunitaire protĂšge notre organisme contre les infections par les bactĂ©ries et les virus. Les globules blancs prĂ©sents dans le sang sont des Ă©lĂ©ments vitaux du systĂšme immunitaire car ils peuvent tuer les bactĂ©ries et les virus. Par ailleurs ils activent d'autres globules blancs, augmentent les dĂ©fenses de l'hĂŽte, et confĂšrent la mĂ©moire immunitaire protĂ©geant de rĂ©infections. Il arrive que le systĂšme immunitaire ne rĂ©ponde pas de façon appropriĂ©e ou ne peut pas contrĂŽler l’infection. Dans ce cas, les globules blancs peuvent causer des dommages collatĂ©raux aux tissus. Cela peut entraĂźner une dĂ©faillance d’organe, associĂ©e Ă  un taux de mortalitĂ© Ă©levĂ©. C'est ce qu'on appelle un sepsis. Avec 50 millions de cas et 11 millions de dĂ©cĂšs par an, le sepsis est une prioritĂ© sanitaire mondiale. Lors d’un sepsis, les globules blancs peuvent cesser de fonctionner ou empĂȘcher le fonctionnement d'autres cellules. C'est ce qu'on appelle l'immunosuppression. Elle peut avoir des effets Ă  long terme chez les patients ayant guĂ©ris d’un sepsis, comme le dĂ©veloppement d’infections et ou de maladies cardiaques. Dans cette thĂšse, nous nous sommes intĂ©ressĂ©s aux globules blancs appelĂ©s cellules myĂ©loĂŻdes suppressives (MDSCs). Les MDSCs restreignent la fonction des autres globules blancs, elles sont donc immunosuppressives. Les personnes en bonne santĂ©, contrairement Ă  celles atteintes de maladies inflammatoires y compris le cancer, ont trĂšs peu de MDSCs dans leur sang. TrĂšs peu Ă©tant connu quant Ă  l’implication des MDSCs dans le sepsis, notre objectif Ă©tait de fournir une analyse approfondie de la dynamique des MDSCs dans des conditions d'infection. Nous avons mis en place quatre Ă©tudes pour rĂ©pondre Ă  notre objectif. Le sang a Ă©tĂ© prĂ©levĂ© Ă  intervalles rĂ©guliers pour mesurer les MDSCs et d'autres paramĂštres immunologiques. La premiĂšre Ă©tude portait sur des volontaires sains recevant une injection d’un morceau de bactĂ©rie simulant un sepsis Ă  bactĂ©rie. Les MDSCs augmentaient rapidement, fortement, et transitoirement revenant Ă  un niveau normal 24 heures aprĂšs l’injection. Dans la deuxiĂšme Ă©tude, nous avons testĂ© des patients sans infection, admis aux soins intensifs (SI). Nous avons remarquĂ© que les patients avec beaucoup de MDSCs dĂ©veloppaient plus d’infections nosocomiales, dont des infections mortelles. Nous pensons que les MDSCs supprimaient la fonction des globules blancs antimicrobiens, augmentant les risques d'infection. Dans la troisiĂšme Ă©tude, nous avons examinĂ© des patients atteints de COVID-19. Les patients COVID-19 admis aux SI avaient plus de MDSCs que ceux n’ayant pas besoin d'ĂȘtre admis aux SI. Dans la quatriĂšme Ă©tude, nous avons analysĂ© des patients atteints de sepsis grave prĂ©sentant une dĂ©faillance de plusieurs organes. Ceux avec beaucoup de MDSCs avaient un pronostique plus favorable. Nous pensons que, dans ce contexte particuliĂšrement sĂ©vĂšre (environ 70% des patients dĂ©cĂ©daient), les MDSCs contrebalançaient la rĂ©ponse excessive de globules blancs et les dommages collatĂ©raux subsĂ©quents. Pour conclure, cette thĂšse dĂ©crit comment les MDSCs sont modulĂ©es pendant un sepsis, et que les MDSCs peuvent ĂȘtre utiles ou nĂ©fastes selon le degrĂ© de sĂ©vĂ©ritĂ© des patients infectĂ©s. Les MDSCs pourraient ĂȘtre utilisĂ©es comme indicateur de gravitĂ© du sepsis, et Ă©ventuellement comme cibles de traitements tels que ceux ciblant les MDSCs testĂ©s actuellement chez les patients cancĂ©reux. -- Het lichaam wordt door zijn eigen immuunsysteem beschermd tegen indringers zoals virussen en bacteriĂ«n. Witte bloedcellen spelen daarbij een belangrijke rol. Ze doden indringers en waarschuwen en activeren andere witte bloedcellen om de afweer te versterken. Soms reageren de witte bloedcellen te sterk of krijgen ze de infectie niet onder controle. In een poging de infectie te bestrijden beschadigen witte bloedcellen dan de weefsels. Deze weefselschade kan leiden tot uitval van organen. De kans op overlijden is hierbij groot. Dit ernstige ziektebeeld wordt sepsis genoemd. Jaarlijks ontwikkelen wereldwijd ongeveer 50 miljoen mensen sepsis waarvan er 11 miljoen overlijden. Na een doorgemaakte sepsis is er kans op langdurige gezondheidsproblemen, zoals bijvoorbeeld nieuwe infecties en hartaandoeningen. Dit komt doordat tijdens sepsis, witte bloedcellen niet alleen te sterk reageren, maar ook stoppen met functioneren en de functie van andere cellen onderdrukken. Dit laatste wordt immunosuppressie genoemd en kan lang aanhouden nadat patiĂ«nten van sepsis hersteld zijn. In dit proefschrift onderzochten we een bepaald type witte bloedcel, namelijk “myeloid-derived suppressor cells” (MDSC's). MDSC's onderdrukken de functie van andere witte bloedcellen en werken dus immunosuppressief. In tegenstelling tot gezonde mensen hebben patiĂ«nten met ontstekingsziekten zoals kanker of auto-immuunziekten veel MDSC’s. Het is echter nog onbekend hoe snel MDSC’s reageren op een infectie en welke rol zij spelen tijdens sepsis. We hebben vier onderzoeken uitgevoerd om hierin meer inzicht te krijgen. De eerste studie betrof gezonde vrijwilligers die stukjes van bacteriĂ«n toegediend kregen. Dit activeert witte bloedcellen en is daarom vergelijkbaar met bacteriĂ«le sepsis. We constateerden dat de MDSC-waarden in het bloed 2 uur na toediening sterk stegen en vervolgens verhoogd bleven tot 8 uur na toediening. Na 24 uur keerden MDSC-waarden terug naar normaal. Hieruit kunnen we concluderen dat MDSC's zeer snel reageren wanneer het lichaam wordt geĂŻnfecteerd door een bacterie. De tweede studie betrof ernstig zieke patiĂ«nten die initieel geen infectie hadden op de intensive care (IC). In deze groep zagen we dat patiĂ«nten met hoge MDSC-waarden een grotere kans hadden om een infectie te ontwikkelen en hierdoor te overlijden. Waarschijnlijk onderdrukten MDSC's de functie van andere infectie-bestrijdende witte bloedcellen, waardoor het infectierisico toenam. De derde studie betrof COVID-19-patiĂ«nten. Sommige COVID-19-patiĂ«nten ontwikkelen sepsis en moeten worden opgenomen in het ziekenhuis. Wij constateerden dat COVID-19-patiĂ«nten die op de IC waren opgenomen, meer MDSC's hadden dan patiĂ«nten die op de verpleegafdeling konden blijven. Ten slotte, onderzochten we in vierde studie patiĂ«nten met ernstige sepsis bij wie meerdere organen waren uitgevallen. Hier constateerden we dat patiĂ«nten met hoge MDSC-waarden een grotere overlevingskans hadden. Hoogstwaarschijnlijk waren MDSC's beschermend bij deze ernstig zieke patiĂ«nten omdat MDSC’s de te hevig reagerende witte bloedcellen onder controle brachten. Concluderend toont dit proefschrift hoe MDSC’s zich gedragen tijdens sepsis, en dat MDSC’s therapeutisch of ziekmakend kunnen werken, afhankelijk van de mate van ontsteking in het lichaam. MDSC-waarden kunnen in de toekomst mogelijk gebruikt worden als maat voor ernst van sepsis, en als aangrijpingspunt voor medicatie

    Atypical developmental trajectories of white matter microstructure in prenatal alcohol exposure: Preliminary evidence from neurite orientation dispersion and density imaging

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    IntroductionFetal alcohol spectrum disorder (FASD), a life-long condition resulting from prenatal alcohol exposure (PAE), is associated with structural brain anomalies and neurobehavioral differences. Evidence from longitudinal neuroimaging suggest trajectories of white matter microstructure maturation are atypical in PAE. We aimed to further characterize longitudinal trajectories of developmental white matter microstructure change in children and adolescents with PAE compared to typically-developing Controls using diffusion-weighted Neurite Orientation Dispersion and Density Imaging (NODDI).Materials and methodsParticipants: Youth with PAE (n = 34) and typically-developing Controls (n = 31) ages 8–17 years at enrollment. Participants underwent formal evaluation of growth and facial dysmorphology. Participants also completed two study visits (17 months apart on average), both of which involved cognitive testing and an MRI scan (data collected on a Siemens Prisma 3 T scanner). Age-related changes in the orientation dispersion index (ODI) and the neurite density index (NDI) were examined across five corpus callosum (CC) regions defined by tractography.ResultsWhile linear trajectories suggested similar overall microstructural integrity in PAE and Controls, analyses of symmetrized percent change (SPC) indicated group differences in the timing and magnitude of age-related increases in ODI (indexing the bending and fanning of axons) in the central region of the CC, with PAE participants demonstrating atypically steep increases in dispersion with age compared to Controls. Participants with PAE also demonstrated greater increases in ODI in the mid posterior CC (trend-level group difference). In addition, SPC in ODI and NDI was differentially correlated with executive function performance for PAE participants and Controls, suggesting an atypical relationship between white matter microstructure maturation and cognitive function in PAE.DiscussionPreliminary findings suggest subtle atypicality in the timing and magnitude of age-related white matter microstructure maturation in PAE compared to typically-developing Controls. These findings add to the existing literature on neurodevelopmental trajectories in PAE and suggest that advanced biophysical diffusion modeling (NODDI) may be sensitive to biologically-meaningful microstructural changes in the CC that are disrupted by PAE. Findings of atypical brain maturation-behavior relationships in PAE highlight the need for further study. Further longitudinal research aimed at characterizing white matter neurodevelopmental trajectories in PAE will be important

    Mushroom ÎČ-glucan and polyphenol formulations as natural immunity boosters and balancers: nature of the application

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    Mushrooms are experiencing a kind of renaissance as a part of the contemporary human diet. These valuable organisms are more than food, they fi t in perfectly as a novel market group known as nutra-mycoceuticals. Immune-balancing mushroom dietary fibers and secondary metabolites such as polyphenols are the main focus of the healthcare industry. Wellness and cosmetic companies are increasingly using mushroom extracts rich in these ingredients. This review considers the basic molecular immunomodulatory mechanisms of action of the most commonly used mushroom dietary fibers, ÎČ-glucans. The literature data on their bioavailability, metabolic transformations, preclinical and human clinical research, and safety are discussed. Immunomodulatory mechanisms of polyphenol ingredients are also considered. These molecules present great potential in the design of the new immunity balancer formulations according to their widespread structural diversity. Finally, we draw attention to the perspectives of modern trends in mushroom nutraceutical and cosmeceutical formulations to strengthen and balance immunity

    Pathogenesis and treatment of chronic rhinosinusitis from the perspective of sinonasal epithelial dysfunction

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    BackgroundChronic rhinosinusitis (CRS) is a clinical syndrome primarily characterized by long-term mucosal inflammation of the nasal cavity and sinuses. The pathogenesis of CRS is still unclear due to its high heterogeneity. A number of studies have recently focused on the sinonasal epithelium. Thus, there has been a quantum leap in awareness of the role of the sinonasal epithelium, which is now understood as an active functional organ rather than simply an inert mechanical barrier. Undoubtedly, epithelial dysfunction plays a vital role in the onset and development of CRS.ObjectiveIn this article, we discuss the potential contribution of sinonasal epithelium dysfunction to CRS pathogenesis and explore a few current and developing therapeutic options targeting the sinonasal epithelium.ResultsImpaired mucociliary clearance (MCC) and an abnormal sinonasal epithelial barrier are usually considered to be the main causative factors in CRS. Epithelial-derived bioactive substances, such as cytokines, exosomes, and complements, play a vital role in the regulation of innate and adaptive immunity and contribute to the pathophysiological alterations of CRS. The phenomena of epithelial–mesenchymal transition (EMT), mucosal remodeling, and autophagy observed in CRS offer some novel insights into the pathogenesis of this disease. In addition, existing treatment options targeting disorder of sinonasal epithelium can help to relieve the main symptoms associated with CRS to some extent.ConclusionThe presence of a normal epithelium is fundamental for maintaining homeostasis in the nasal and paranasal sinuses. Here, we describe various aspects of the sinonasal epithelium and highlight the contributions of epithelial dysfunction to CRS pathogenesis. Our review provides sound evidence of the need for in-depth study of the pathophysiological alterations of this disease and for the development of novel epithelium-targeting alternative treatments

    IDO1 and inflammatory neovascularization: bringing new blood to tumor-promoting inflammation

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    In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the ‘Hallmarks of Cancer’, it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies

    Multiple functions and regulatory network of miR-150 in B lymphocyte-related diseases

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    MicroRNAs (miRNAs) play vital roles in the post-transcriptional regulation of gene expression. Previous studies have shown that miR-150 is a crucial regulator of B cell proliferation, differentiation, metabolism, and apoptosis. miR-150 regulates the immune homeostasis during the development of obesity and is aberrantly expressed in multiple B-cell-related malignant tumors. Additionally, the altered expression of MIR-150 is a diagnostic biomarker of various autoimmune diseases. Furthermore, exosome-derived miR-150 is considered as prognostic tool in B cell lymphoma, autoimmune diseases and immune-mediated disorders, suggesting miR-150 plays a vital role in disease onset and progression. In this review, we summarized the miR-150-dependent regulation of B cell function in B cell-related immune diseases

    Variable optical elements for fast focus control

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    In this Review, we survey recent developments in the emerging field of high-speed variable-z-focus optical elements, which are driving important innovations in advanced imaging and materials processing applications. Three-dimensional biomedical imaging, high-throughput industrial inspection, advanced spectroscopies, and other optical characterization and materials modification methods have made great strides forward in recent years due to precise and rapid axial control of light. Three state-of-the-art key optical technologies that enable fast z-focus modulation are reviewed, along with a discussion of the implications of the new developments in variable optical elements and their impact on technologically relevant applications

    Electrically-evoked responses for retinal prostheses are differentially altered depending on ganglion cell types in outer retinal neurodegeneration caused by Crb1 gene mutation

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    BackgroundMicroelectronic prostheses for artificial vision stimulate neurons surviving outer retinal neurodegeneration such as retinitis pigmentosa (RP). Yet, the quality of prosthetic vision substantially varies across subjects, maybe due to different levels of retinal degeneration and/or distinct genotypes. Although the RP genotypes are remarkably diverse, prosthetic studies have primarily used retinal degeneration (rd) 1 and 10 mice, which both have Pde6b gene mutation. Here, we report the electric responses arising in retinal ganglion cells (RGCs) of the rd8 mouse model which has Crb1 mutation.MethodsWe first investigated age-dependent histological changes of wild-type (wt), rd8, and rd10 mice retinas by H&E staining. Then, we used cell-attached patch clamping to record spiking responses of ON, OFF and direction selective (DS) types of RGCs to a 4-ms-long electric pulse. The electric responses of rd8 RGCs were analyzed in comparison with those of wt RGCs in terms of individual RGC spiking patterns, populational characteristics, and spiking consistency across trials.ResultsIn the histological examination, the rd8 mice showed partial retinal foldings, but the outer nuclear layer thicknesses remained comparable to those of the wt mice, indicating the early-stage of RP. Although spiking patterns of each RGC type seemed similar to those of the wt retinas, correlation levels between electric vs. light response features were different across the two mouse models. For example, in comparisons between light vs. electric response magnitudes, ON/OFF RGCs of the rd8 mice showed the same/opposite correlation polarity with those of wt mice, respectively. Also, the electric response spike counts of DS RGCs in the rd8 retinas showed a positive correlation with their direction selectivity indices (r = 0.40), while those of the wt retinas were negatively correlated (r = −0.90). Lastly, the spiking timing consistencies of late responses were largely decreased in both ON and OFF RGCs in the rd8 than the wt retinas, whereas no significant difference was found across DS RGCs of the two models.ConclusionOur results indicate the electric response features are altered depending on RGC types even from the early-stage RP caused by Crb1 mutation. Given the various degeneration patterns depending on mutation genes, our study suggests the importance of both genotype- and RGC type-dependent analyses for retinal prosthetic research

    Identifizierung prÀdiktiver und prognostischer Biomarker in unterschiedlichen Tumorkompartimenten des ösophagealen Adenokarzinoms

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    Das ösophageale Adenokarzinom zeigt eine global steigende Inzidenz und hat mit einer 5-Jahres-Überlebensrate von weniger als 25% eine schlechte Prognose. Personalisierte TherapieansĂ€tze sind selten und prognostische/prĂ€diktive Biomarker des Tumormikromilieus sind unzureichend charakterisiert. Die kumulative Promotion nĂ€hert sich dieser Problematik in drei unterschiedlichen Schwerpunkten. 1. Zur Identifizierung Kompartiment-spezifischer Biomarker wurde eine Methode entwickelt, welche als kostengĂŒnstige Alternative zum sc-Seq Expressionsprofile individueller Zelltypen generiert. Dabei erfolgt die Extraktion der RNA nicht aus Einzelzellen, sondern aus flowzytometrisch-getrennten Zellkompartimenten. Die Separation der Proben in Epithelzellen, Immunzellen und Fibroblasten wurde durch verschiedene Verfahren validiert und eine suffiziente Ausbeute an RNA auch fĂŒr kleine Gewebemengen gezeigt. 2. Biomarker des Immunzellkompartiments als therapeutische Angriffspunkte wurden in einem Patientenkollektiv von bis zu 551 Patienten auf ihre Bedeutung beim EAC ĂŒberprĂŒft. Es zeigte sich eine Expression der Immuncheckpoints LAG3, VISTA und IDO auf TILs durch IHC und RNA-Sonden basierte Verfahren in einem relevanten Anteil (LAG3: 11,4%, VISTA: 29%, IDO: 52,6%). Es konnte eine prognostisch gĂŒnstige Bedeutung der VISTA, LAG3 und IDO Expression gezeigt werden. Durch den Vergleich von Genexpressionsprofilen aus therapienaiven und vorbehandelten Tumoren konnte zudem ein immunsuppressiver Effekt von neoadjuvanten Therapiekonzepten auf das Tumormikromilieu des EACs gezeigt werden. Dabei kam es zur verminderten Expression von Checkpoints und Anzahl TILs nach (Radio-) Chemotherapie. 3. Im Tumorzellkompartiment wurde die Rolle von Amplifikationen in ErbB-Rezeptor abhĂ€ngigen Signalwegen durch FISH-Technik und Immunhistochemie evaluiert. Es fanden sich KRAS Amplifikationen in 17,1%, PIK3CA Amplifikationen in 5% sowie eine HER2/neu-Überexpression in 14,9% der untersuchten Tumore
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