The receptor RAGE: Bridging inflammation and cancer

The receptor for advanced glycation end products (RAGE) is a single transmembrane receptor of the immunoglobulin superfamily that is mainly expressed on immune cells, neurons, activated endothelial and vascular smooth muscle cells, bone forming cells, and a variety of cancer cells. RAGE is a multifunctional receptor that binds a broad repertoire of ligands and mediates responses to cell damage and stress conditions. It activates programs responsible for acute and chronic inflammation, and is implicated in a number of pathological diseases, including diabetic complications, stroke, atheriosclerosis, arthritis, and neurodegenerative disorders. The availability of Rage knockout mice has not only advanced our knowledge on signalling pathways within these pathophysiological conditions, but also on the functional importance of the receptor in processes of cancer. Here, we will summarize molecular mechanisms through which RAGE signalling contributes to the establishment of a pro-tumourigenic microenvironment. Moreover, we will review recent findings that provide genetic evidence for an important role of RAGE in bridging inflammation and cancer

Identification of the Rage-dependent gene regulatory network in a mouse model of skin inflammation

<p>Abstract</p> <p>Background</p> <p>In the past, molecular mechanisms that drive the initiation of an inflammatory response have been studied intensively. However, corresponding mechanisms that sustain the expression of inflammatory response genes and hence contribute to the establishment of chronic disorders remain poorly understood. Recently, we provided genetic evidence that signaling via the receptor for advanced glycation end products (Rage) drives the strength and maintenance of an inflammatory reaction. In order to decipher the mode of Rage function on gene transcription levels during inflammation, we applied global gene expression profiling on time-resolved samples of mouse back skin, which had been treated with the phorbol ester TPA, a potent inducer of skin inflammation.</p> <p>Results</p> <p>Ranking of TPA-regulated genes according to their time average mean and peak expression and superimposition of data sets from wild-type (<it>wt</it>) and <it>Rage</it>-deficient mice revealed that Rage signaling is not essential for initial changes in TPA-induced transcription, but absolutely required for sustained alterations in transcript levels. Next, we used a data set of differentially expressed genes between TPA-treated <it>wt </it>and <it>Rage</it>-deficient skin and performed computational analysis of their proximal promoter regions. We found a highly significant enrichment for several transcription factor binding sites (TFBS) leading to the prediction that corresponding transcription factors, such as Sp1, Tcfap2, E2f, Myc and Egr, are regulated by Rage signaling. Accordingly, we could confirm aberrant expression and regulation of members of the E2f protein family in epidermal keratinocytes of Rage-deficient mice.</p> <p>Conclusions</p> <p>In summary, our data support the model that engagement of Rage converts a transient cellular stimulation into sustained cellular dysfunction and highlight a novel role of the Rb-E2f pathway in Rage-dependent inflammation during pathological conditions.</p

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

40. NAR-Seminar. Soziale Beziehungen im Alter : Mein Mann ist zwar etwas dünn und klapprig, aber...? Ambivalenzen in jahrzehntelangen Paarbeziehungen

Im Titelzitat „Mein Mann ist zwar etwas dünn und klapprig, aber...“ kommt eine Ambivalenz zum Ausdruck, die häufig in den Aussagen älterer und alter Paare vermittelt wird. Sind wir enttäuscht über eine solche Aussage nach jahrzehntelanger Beziehung? Mutet dieses Zitat eventuell sogar etwas absurd an? Einerseits kann man sich wundern, andererseits könnte die Aussage Ausdruck einer vielschichtigen Komplexität sein, in der ein über Jahrzehnte austarierter Prozess zum Ausdruck kommt, der viele paarspezifische Themen erfolgreich regelt

Keine Lust mehr? Zur Sexualität von Paaren nach der Lebensmitte

Lange Zeit gingen Wissenschaftler davon aus, das Lebensalter sei entscheidend für das Ausmaß an sexueller Aktivität. Inzwischen wissen wir jedoch, dass die Sexualität eines Paares sehr viel stärker durch die Dauer der Beziehung als durch das Alter der Partner gedämpft wird; zumindest bis zum 50. Lebensjahr, vermutlich sogar länger. Das bedeutet: Ältere Paare in jungen Beziehungen führen in der Regel ein deutlich aktiveres Sexualleben als ältere Paare in Langzeitbeziehungen. Letztere beenden ihre gemeinsame Sexualität häufig, bevor die sexuellen Möglichkeiten erschöpft sind. Dies ist bedauerlich – behält die Sexualität zumeist doch eine zentrale Bedeutung für Wohlbefinden, Vitalität und Lebenszufriedenheit, auch für das Erleben von Nähe, Wärme und Geborgen- heit in der Paarbeziehung

Was ist linguistische Evidenz? Kolloquium des Zentrums Sprachenvielfalt und Mehrsprachigkeit, November 2006

Der zweite Band der Reihe des Zentrums Sprachenvielfalt und Mehrsprachigkeit (ZSM) der Universität zu Köln enthält die Beiträge des Kolloquiums "Was ist linguistische Evidenz?". Die Beiträge stammen aus verschiedenen sprachwissenschaftlichen Disziplinen (Allgemeine Sprachwissenschaft, Anglistik, Sprachliche Informationsverarbeitung, Phonetik und Psycholinguistik) und widmen sich der Frage des Kolloquiums aus verschiedenen Perspektiven. Behandelt werden grundsätzliche Diskussionen über den Zusammenhang von Evidenz und sprachwissenschaftlichen Theorien, experimentelle Paradigmen (Priming-Experimente, Eye-Tracking-Experimente, Thermometerverfahren), computergesteuerte Korpusanalyse und Herausforderungen bei der Datengewinnung durch Feldforschung

The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor

Two related models for T cell signalling initiation suggest either that T cell receptor (TCR) engagement leads to its recruitment to ordered membrane domains, often referred to as lipid rafts, where signalling molecules are enriched or that ordered TCR-containing membrane nanodomains coalesce upon TCR engagement. That ordered domains form upon TCR engagement, as they do upon lipid raft marker patching, has not been considered. The target of this study was to differentiate between those three options. Plasma membrane order was followed in live T cells at 37 °C using laurdan to report on lipid packing. Patching of the TCR that elicits a signalling response resulted in aggregation, not formation, of ordered plasma membrane domains in both Jurkat and primary T cells. The TCR colocalised with actin filaments at the plasma membrane in unstimulated Jurkat T cells, consistent with it being localised to ordered membrane domains. The colocalisation was most prominent in cells in G1 phase when the cells are ready to commit to proliferation. At other cell cycle phases the TCR was mainly found at perinuclear membranes. Our study suggests that the TCR resides in ordered plasma membrane domains that are linked to actin filaments and aggregate upon TCR engagement

The T cell receptor resides in ordered plasma membrane nanodomains that aggregate upon patching of the receptor

Two related models for T cell signalling initiation suggest either that T cell receptor (TCR) engagement leads to its recruitment to ordered membrane domains, often referred to as lipid rafts, where signalling molecules are enriched or that ordered TCR-containing membrane nanodomains coalesce upon TCR engagement. That ordered domains form upon TCR engagement, as they do upon lipid raft marker patching, has not been considered. The target of this study was to differentiate between those three options. Plasma membrane order was followed in live T cells at 37 °C using laurdan to report on lipid packing. Patching of the TCR that elicits a signalling response resulted in aggregation, not formation, of ordered plasma membrane domains in both Jurkat and primary T cells. The TCR colocalised with actin filaments at the plasma membrane in unstimulated Jurkat T cells, consistent with it being localised to ordered membrane domains. The colocalisation was most prominent in cells in G1 phase when the cells are ready to commit to proliferation. At other cell cycle phases the TCR was mainly found at perinuclear membranes. Our study suggests that the TCR resides in ordered plasma membrane domains that are linked to actin filaments and aggregate upon TCR engagement