Oral squamous cell carcinoma detection by salivary biomarkers in a Serbian population

Early detection of oral squamous cell cancer (OSCC) is the key to improve the low 5-year survival rate. Using proteomic and genomic technologies we have previously discovered and validated salivary OSCC markers in American patients. The question arises whether these biomarkers are discriminatory in cohorts of different ethnic background. Six transcriptome (DUSP1, IL8, IL1B, OAZ1, SAT1, and S100P) and three proteome (IL1B, IL8, and M2BP) biomarkers were tested on 18 early and 17 late stage OSCC patients and 51 healthy controls with quantitative PCR and ELISA. Four transcriptome (IL8, IL1B, SAT1, and S100P) and all proteome biomarkers were significantly elevated (p lt 0.05) in OSCC patients. The combination of markers yielded an AUC of 0.86, 0.85 and 0.88 for OSCC total, T1-T2, and T3-T4, respectively. The sensitivity/specificity for OSCC total was 0.89/0.78, for T1-T2 0.67/0.96, and for T3-T4 0.82/0.84. In conclusion, seven of the nine salivary biomarkers (three proteins and four mRNAs) were validated and performed strongest in late stage cancer. Patient-based salivary diagnostics is a highly promising approach for OSCC detection. This study shows that previously discovered and validated salivary OSCC biomarkers are discriminatory and reproducible in a different ethnic cohort. These findings support the feasibility to implement multi-center, multi-ethnicity clinical trials towards the pivotal validation of salivary biomarkers for OSCC detection

Administration of Panobinostat Is Associated with Increased IL-17A mRNA in the Intestinal Epithelium of HIV-1 Patients

Intestinal CD4+ T cell depletion is rapid and profound during early HIV-1 infection.This leads to a compromised mucosal barrier that prompts chronic systemic inflammation.The preferential loss of intestinal T helper 17 (Th17) cells in HIV-1 disease is a driver of the damage within the mucosal barrier and of disease progression.Thus, understanding the effects of new therapeutic strategies in the intestines has high priority. Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are actively under investigation as potential latency reversing agents in HIV eradication studies. These drugs have broad effects that go beyond reactivating virus, including modulation of immune pathways. We examined colonic biopsies from ART suppressed HIV-1 infected individuals (clinicaltrials.gov: NCT01680094) for the effects of panobinostat on intestinal T cell activation and on inflammatory cytokine production. We compared biopsy samples that were collected before and during oral panobinostat treatment and observed that panobinostat had a clear biological impact in this anatomical compartment. Specifically, we observed a decrease in CD69+ intestinal lamina propria T cell frequency and increased IL-17A mRNA expression in the intestinal epithelium. These results suggest that panobinostat therapy may influence the restoration of mucosal barrier function in these patients

Administration of Panobinostat Is Associated with Increased IL-17A mRNA in the Intestinal Epithelium of HIV-1 Patients

Intestinal CD4+ T cell depletion is rapid and profound during early HIV-1 infection. This leads to a compromised mucosal barrier that prompts chronic systemic inflammation. The preferential loss of intestinal T helper 17 (Th17) cells in HIV-1 disease is a driver of the damage within the mucosal barrier and of disease progression. Thus, understanding the effects of new therapeutic strategies in the intestines has high priority. Histone deacetylase (HDAC) inhibitors (e.g., panobinostat) are actively under investigation as potential latency reversing agents in HIV eradication studies. These drugs have broad effects that go beyond reactivating virus, including modulation of immune pathways. We examined colonic biopsies from ART suppressed HIV-1 infected individuals (clinicaltrials.gov: NCT01680094) for the effects of panobinostat on intestinal T cell activation and on inflammatory cytokine production. We compared biopsy samples that were collected before and during oral panobinostat treatment and observed that panobinostat had a clear biological impact in this anatomical compartment. Specifically, we observed a decrease in CD69+ intestinal lamina propria T cell frequency and increased IL-17A mRNA expression in the intestinal epithelium. These results suggest that panobinostat therapy may influence the restoration of mucosal barrier function in these patients

GreenTwin: Developing a Digital Twin for Sustainable Cooperative Mobility and Logistics in Rural Areas

Public transportation is often poorly developed, especially in rural areas, which leads to an increased dependence on personal vehicles. Moreover, since transportation is one of the main drivers of climate change, our research project aims to explore cost-effective methods for sustainable last-mile logistics in rural areas and support decision-makers utilizing a dashboard. For this purpose, an open marketplace platform is planned that intelligently networks suppliers and service providers in a region and bundles orders and deliveries. The aim is also to motivate customers and users to behave in a more environmentally friendly way by suggesting appropriate offers through the way they are presented on the marketplace. This is achieved by integrating Digital Twin (DT) technologies, cognitive agent-based social simulation, transport management systems and recommendation systems. To ensure the project aligns with public needs and acceptance of proposed approaches, we conduct census-representative surveys alongside the development and experimentation phases. In this paper, the overall structure of the research project and the submodels underpinning our solution are introduced. It also includes a visual mockup of a rural region’s DT and introduces several use cases

Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1tg-type I) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1tg-type I mice showed normal memory performance, but in older NRG1tg-type I mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1tg-type I mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1tg-type I mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform

ARTEFACTS: How do we want to deal with the future of our one and only planet?

The European Commission’s Science and Knowledge Service, the Joint Research Centre (JRC), decided to try working hand-in-hand with leading European science centres and museums. Behind this decision was the idea that the JRC could better support EU Institutions in engaging with the European public. The fact that European Union policies are firmly based on scientific evidence is a strong message which the JRC is uniquely able to illustrate. Such a collaboration would not only provide a platform to explain the benefits of EU policies to our daily lives but also provide an opportunity for European citizens to engage by taking a more active part in the EU policy making process for the future. A PILOT PROGRAMME To test the idea, the JRC launched an experimental programme to work with science museums: a perfect partner for three compelling reasons. Firstly, they attract a large and growing number of visitors. Leading science museums in Europe have typically 500 000 visitors per year. Furthermore, they are based in large European cities and attract local visitors as well as tourists from across Europe and beyond. The second reason for working with museums is that they have mastered the art of how to communicate key elements of sophisticated arguments across to the public and making complex topics of public interest readily accessible. That is a high-value added skill and a crucial part of the valorisation of public-funded research, never to be underestimated. Finally museums are, at present, undergoing something of a renaissance. Museums today are vibrant environments offering new techniques and technologies to both inform and entertain, and attract visitors of all demographics.JRC.H.2-Knowledge Management Methodologies, Communities and Disseminatio

Global monitoring of antimicrobial resistance based on metagenomics analyses of urban sewage

Antimicrobial resistance (AMR) is a serious threat to global public health, but obtaining representative data on AMR for healthy human populations is difficult. Here, we use meta-genomic analysis of untreated sewage to characterize the bacterial resistome from 79 sites in 60 countries. We find systematic differences in abundance and diversity of AMR genes between Europe/North-America/Oceania and Africa/Asia/South-America. Antimicrobial use data and bacterial taxonomy only explains a minor part of the AMR variation that we observe. We find no evidence for cross-selection between antimicrobial classes, or for effect of air travel between sites. However, AMR gene abundance strongly correlates with socio-economic, health and environmental factors, which we use to predict AMR gene abundances in all countries in the world. Our findings suggest that global AMR gene diversity and abundance vary by region, and that improving sanitation and health could potentially limit the global burden of AMR. We propose metagenomic analysis of sewage as an ethically acceptable and economically feasible approach for continuous global surveillance and prediction of AMR.Peer reviewe

Gefäßfunktion der atherosklerotischen, LDL-Rezeptor-defizienten Apolipoprotein-B100-only-Maus

1\. Introduction and derivation of the question Atherosclerosis is a major health problem. It is the most important underlying cause of cardiovascular disease, which is the main cause of death among European men under 65 and the second most common cause of death among European women. Atherosclerosis is a chronic, slowly progressing, non-reversible disease affecting the blood vessel walls leading to a "hardening" or "stiffening" of the arteries. The etiopathological connection between atherosclerosis and high blood cholesterol levels has been established in many studies. Different animal models have been used to explore the underlying mechanisms and characteristics of this disease and have generated inconsistent results. The lipid profiles of these models were often different to that observed in the human atherogenic lipid profile and thus did not appropriately reflect the pathogenesis of human atherosclerosis. Recently, the B6;129S-ApoBtm2SgyLdlrtm1Her mouse (ApoB mouse) was developed. It is an atherosclerotic double-knock-out low-density- lipoprotein-receptor-deficient apolipoprotein-B-100-only mouse. This mouse model has a lipid profile similar to most humans suffering from atherosclerosis. Using the ApoB mouse model, we explored the changes in vasoreactivity during the process of atherosclerotic alteration. For a further characterization of this mouse model, lipid profile and adhesion molecules were measured and morphometric evaluation of the research vessels was performed. 2\. Materials and methods Male ApoB mice and B6129SF2/J mice (B6 wild type, control mice) were examined at age 4 months (young group) or 18 months (old group). 2 mm ring preparations of the root of the aorta thoracica and of the main branch of the arteria mesenterica superior were mounted on tungsten wires into separate organ chambers of a myograph (Mulvany apparatus). Vessels were kept at 36.7°C in a physiological Krebs-Henseleit solution. Contraction was measured under isometric conditions. Phenylephrine, angiotensin II, acetylcholine (with and without indomethacin incubation), and DEA NONOate (NO donor) were applied in a cumulative concentration response manner. Contractile responses to phenylephrine and angiotensin II were presented as a percentage of K+ response. Responses to the vasodilators acetylcholine and DEA NONOate were investigated after submaximal phenylephrine contraction. Cholesterol and triglyceride serum levels were measured using enzymatic colorimetric assays. The distribution of cholesterol among the lipoprotein subclasses was determined using a Superose 6 column. sICAM-1 and sVCAM-1 were examined by immunoassay. The stenosis rate of the vessel lumen was quantified after Giemsa staining of paraffin sections with the assistance of a digitizing morphometry image-analysis system. 3\. Results Morphometric analysis showed that all old ApoB mice had developed severe atherosclerosis in the aorta while the arteria mesenterica superior was unaffected. More than half of the lumen of the aorta thoracica of the old ApoB mice was covered with atherosclerotic plaques. Young ApoB mice as well as B6 wild type mice generally did not show signs of atherosclerosis using light microscopy. In the atherosclerotic aorta of the old ApoB mice, vessels had a reduced response to K+ and angiotensin II compared with the respective old B6 wild type mice and compared with the young ApoB mice. The vessel reactivity to these agonists was unchanged in the non-atherosclerotic arteria mesenterica superior of the young and old ApoB mice. In contrast, phenylephrine reactivity was diminished to the same degree in both aorta and arteria mesenterica superior of young and old ApoB groups when compared to the B6 wild type mice. Acetylcholine-induced, endothelium dependent dilation was reduced in the aorta of the old ApoB mice compared to young ApoB mice and wild type controls. The arteria mesenterica superior of the ApoB mice strain responded stronger to acetylcholine than the B6 mice strain. In the aorta, endothelium independent dilation to DEA NONOate was alike in all groups. The arteria mesenterica superior of the young ApoB mice dilated more strongly in response to low dose DEA NONOate compared to young B6 mice. No other groups differed in the DEA NONOate response. Acetylcholine-induced vasodilation was slightly impaired after indomethacin incubation in the young ApoB mice. Indomethacin treatment did not influence reactions to acetylcholine in the arteria mesenterica superior of the ApoB strain. Serum parameters showed a rise in total cholesterol and triglycerides in the ApoB strain compared to B6 control mice. The LDL fraction within the lipoprotein profile was markedly increased. The old ApoB group also showed an increase in the total serum cholesterol and VLDL compared to the young ApoB and B6 wild type mice. sICAM-1 and sVCAM-1 were increased in the old ApoB group compared to the young ApoB mice. sVCAM-1 concentration was also greater in both ApoB groups compared to their respective B6 wild type mice. Further, sICAM-1 was increased in the old B6 compared to young B6 mice. 4\. Conclusions The atherosclerotic ApoB mouse model demonstrated severe atherosclerotic changes in the aorta but not in the arteria mesenterica superior. This genetic model also demonstrates the importance of age, since young ApoB mice did not show morphological alterations of the aorta using light microscopy. The study shows that atherosclerotic alterations of the aorta of ApoB mice coincide with a diminished vasoreaction to K+, angiotensin II, and acetylcholine. Remarkably, the phenylephrine response was attenuated already to the same degree in the non-atherosclerotic aorta of the young ApoB mice as in the atherosclerotic aorta of the ApoB old group. Moreover, the phenylephrine- induced constriction was also reduced in the non-atherosclerotic arteria mesenterica superior. This suggests changes in receptor expression and/or signaling pathway for adrenergic receptors in both types of vessels, which may develop before the occurrence of structural changes in the arterial wall of ApoB mice. Concurrently, the endothelium-independent vasodilative capacity was unchanged (DEA NONOate). Our data supports the idea of a special role of the adrenergic system for atherosclerosis related changes of vessel function in ApoB mice. Reduced endothelium dependent relaxation to acetylcholine in the aorta of ApoB old mice underlines the morphological finding of impairment of the endothelium in this vessel of ApoB mice during aging. We conclude from the vessel reactions that of all applied pharmacological substances acetylcholine is the most useful substance to test atherosclerotic alterations in the ApoB mice model. The data further indicates no involvement of COX-products in the altered function of the atherosclerotic aorta. This study provides original data about vessel function, morphology, and serum parameters in ApoB mice, thereby giving a first insight into the pathogenesis of atherosclerosis related impairment of arterial vessel function in this model.1\. Einleitung und Herleitung der Fragestellung Atherosklerose ist ein großes Gesundheitsproblem und die wichtigste Ursache kardiovaskulärer Erkrankungen. Diese stellen die häufigste Todesursache europäischer Männer unter 65 und die zweithäufigste Todesursache europäischer Frauen dar. Bei der Atherosklerose handelt es um eine chronische, langsam voranschreitende und irreversible Erkrankung, die zur Verhärtung der ateriellen Blutgefäßwände führt. Die ätiopathologische Verbindung zwischen Atherosklerose und insbesondere hohem Blutcholesterol wurde in vielen Studien gezeigt. In der Vergangenheit wurden unterschiedliche Tiermodelle verwendet, um die zugrundeliegenden Mechanismen und Eigenschaften dieser Erkrankung zu beschreiben. Häufig waren die Ergebnisse inkonsistent. Die verwendeten Tiermodelle wiesen oft stark abweichende Lipidprofile im Vergleich zum atherogenen humanen Lipidprofil auf und ermöglichten nur deutlich eingeschränkte Aussagen zur Pathogenese humaner Atherosklerose. In jüngerer Zeit wurde die B6;129A-ApoBtm2SgyLdlrtm1Her-Maus (ApoB-Maus) entwickelt. Es handelt sich hierbei um eine LDL-Rezeptor- defiziente, „apolipoprotein-B-100-only” doppel-knock-out Maus. Durch die genetische Modifikation hat diese Maus ein Lipidprofil, das dem der meisten Menschen ähnlich ist, die an Atherosklerose leiden. In der vorliegenden Arbeit wurde mit dem ApoB-Mausmodell die Veränderung der Gefäßansprechbarkeit während der Entwicklung einer Atherosklerose untersucht. Zur weiteren Beschreibung der ApoB-Maus wurden das Lipidprofil sowie die Adhäsionsmoleküle bestimmt. Des Weiteren wurde eine morphometrische Evaluation der untersuchten Gefäße vorgenommen. 2\. Materialien und Methoden Männliche ApoB-Mäuse und B6129SF2/J-Mäuse (B6-Wildtyp, Kontrollmäuse) wurden im Alter von 4 Monaten (junge Gruppen) oder 18 Monaten (alte Gruppen) untersucht. Jeweils eine 2 mm Ring-Präparation der Aortenwurzel und des Hauptastes der Arteria mesenterica superior wurden auf Wolfram-Drähten in zwei getrennte Myographen-Kammern eingebracht (Mulvany-Apparat). Die Blutgefäße befanden sich im Myographen in 36,7°C warmer physiologischer Krebs-Henseleit-Lösung. Die Gefäßkontraktionen wurden unter isometrischen Bedingungen gemessen. Phenylephrin, Angiotensin II, Acetylcholin (mit und ohne Indomethacin-Inkubation) und DEA NONOate (NO-Donor) wurden im Sinne einer kumulativen Konzentrations-Wirkungs-Kurve in die Badlösung appliziert. Die Stärke der kontraktilen Antworten auf die Phenylephrin- sowie Angiotensin II-Gabe wurden in Prozent der K+-Antwort angegeben. Die Reaktionen auf die Gefäßdilatoren Acetylcholin sowie DEA NONOate wurden nach der Auslösung einer submaximalen Phenylephrin-Kontraktion untersucht. Die Cholesterol- und Triglyzeridkonzentrationen im Serum wurden mit Hilfe enzymatischer kolorimetrischer Assays bestimmt. Die Verteilung des Cholesterols auf die Lipoprotein-Subklassen wurde mit einer Superose-6-Säule ermittelt. sICAM-1 und sVCAM-1 wurden mit einem Immuno-Assay gemessen. Der Stenosierungsgrad der Gefäßlumen wurde nach Giemsa-Färbung an Paraffinschnitten mit Hilfe eines digitalen morphometrischen Bildanalysesystems quantifiziert. 3\. Ergebnisse Die morphometrische Analyse ergab starke atherosklerotische Veränderungen der Aorten aller alten ApoB- Mäuse, während die Arteria mesenterica superior stets unbetroffen war. Mehr als die Hälfte des Lumens der Aorta thoracica dieser Mäuse war mit atherosklerotischen Plaques bedeckt. Sowohl junge ApoB-Mäuse als auch der B6-Wildtyp zeigten keine lichtmikroskopischen atherosklerotischen Veränderungen. In der atherosklerotischen Aorta der alten ApoB-Mäuse war die Antwort auf K+ und Angiotensin II im Vergleich zu den alten B6-Mäusen und den jungen ApoB-Mäusen verringert. Die Gefäßreaktivität auf diese Agonisten war unverändert in der nicht-atherosklerotischen Arteria mesenterica superior der jungen und alten ApoB-Mäuse. Im Gegensatz hierzu war die Reaktion auf Phenylephrin sowohl in der Aorta als auch in der Arteria mesenterica superior der jungen sowie alten ApoB-Mäuse im Vergleich zum B6-Wildtyp vermindert. Die acetylcholininduzierte, endothelabhängige Dilation war in der Aorta der alten ApoB-Mäuse im Vergleich zu den jungen ApoB-Mäusen und dem B6-Wildtyp reduziert. Die Arteria mesenterica superior der ApoB-Mäuse zeigte nach Acetylcholin-Gabe stärkere Antworten als der B6-Wildtyp. In der Aorta war die endothelunabhängige, durch DEA NONOate ausgelöste Vasodilation in den ApoB- Gruppen ähnlich und unterschied sich nicht vom B6-Wildtyp. Die Arteria mesenterica superior der jungen ApoB-Mäuse dilatierte bei geringen DEA NONOate-Dosen stärker als die des B6-Wildtyps. Die anderen Gruppen zeigten keine Unterschiede. In der Aorta der jungen ApoB-Mäuse führte die Indomethacin-Inkubation zu einer leichten Hemmung der Acetylcholin-Antwort. In der Arteria mesenterica superior der ApoB-Mäuse hatte die Inkubation keinen Einfluss. Die Serumparameter zeigten einen Anstieg im Cholesterol- und Triglyzeridspiegel im ApoB-Stamm im Vergleich zum B6-Wildtyp. Innerhalb des Lipoproteinprofiles stieg besonders die LDL-Fraktion an. Die alten ApoB-Mäuse zeigten darüber hinaus einen weiteren Anstieg des Gesamt-Serum-Cholesterols sowie der VLDL-Fraktion im Vergleich zu den jungen ApoB-Mäusen und zum B6-Wildtyp. sICAM-1 und sVCAM-1 waren in der alten ApoB-Gruppe im Vergleich zur jungen ApoB-Gruppe erhöht. Darüber hinaus war sVCAM-1 in beiden ApoB- Gruppen im Vergleich zum B6-Wildtyp erhöht. sICAM-1 zeigte außerdem einen Anstieg in der alten B6-Gruppe im Vergleich zur jungen B6-Gruppe. 4\. Schlussfolgerungen Das atherosklerotische ApoB-Mausmodell zeigte starke pathologische Veränderungen in der Aorta und keine in der Arteria mesenterica superior. Dieses genetisch modifizierte Modell lässt darüber hinaus eine Altersabhängigkeit erkennen, da junge ApoB-Mäuse keine lichtmikroskopischen Veränderungen der Aorta aufwiesen. Die Studie zeigt, dass atherosklerotische Veränderungen der Aorta der ApoB-Maus mit verminderter Gefäßreaktivität auf K+, Angiotensin II sowie Acetylcholin einhergehen. Bemerkenswerterweise war die Phenylephrin-Antwort in der nicht-atherosklerotischen Aorta der jungen Apo-Gruppe sowie in der atherosklerotischen Aorta der alten ApoB-Gruppe in gleichem Maße stark vermindert. Des Weiteren war die phenylephrininduzierte Kontraktion ebenso in der nicht-atherosklerotischen Arteria mesenterica des ApoB-Stamms reduziert. Dies weist darauf hin, dass es Veränderungen in der Rezeptor-Expression und/oder den Signalwegen für adrenerge Rezeptoren in beiden Blutgefäßtypen gibt, die bereits vor dem Auftreten struktureller Veränderungen in der arteriellen Wand der ApoB-Maus auftreten. Gleichzeitig war die endothelunabhängige vasodilative Kapazität unverändert (DEA NONOate). Die Daten weisen darauf hin, dass das adrenerge Sytem in Bezug auf atheroskleroseinduzierte Veränderungen der Gefäßfunktion der ApoB-Maus eine besondere Rolle spielt. Die reduzierte endothelabhängige Acetylcholinantwort in der Aorta der alten ApoB-Mäuse und die morphologischen Befunde des atherosklerotischen Befalls weisen auf eine Beeinträchtigung der Endothelfunktion dieses Gefäßes während des Altersgangs in diesem Tiermodell hin. Wir schließen aus den Gefäßreaktionen, dass von den verwendeten pharmakologischen Substanzen Acetylcholin am besten zur Charakterisierung der atherosklerotischen Veränderungen der ApoB-Maus geeignet ist. Die Daten ergeben keine Anhaltspunkte für eine Beteiligung von COX-Produkten in der atherosklerotisch veränderten Funktion der Aorta. In dieser Studie wurde erstmals die Gefäßfunktion in Gegenüberstellung zu Serumparametern und Morphologie der Aorta und Arteria mesenterica superior von ApoB-Mäusen untersucht. Sie gestattet erste Einblicke in die atherosklerosebedingte Pathogenese der arteriellen Gefäßfunktion in diesem Mausmodell