Induction of interleukin-10 within the T(H)17 effector population using the GPER agonist G-1

A critical mechanism in immune homeostasis is the ability to stop an ongoing inflammatory response once the inciting agent has been destroyed or neutralized. Failure to do so can lead to autoimmune disease. One mechanism the immune system utilizes to self regulate is the secretion of immunosuppressive cytokines. For example, the cytokine interleukin-10 (IL10) is a potent suppressor of numerous key immune cell populations. Among the cells that secrete IL10 are several subsets of the CD4+ T cell family. As CD4+ T cells are commonly found within diseased tissue in the setting of autoimmune disease, medications capable of inducing IL10 expression in local CD4+ T populations would be of great therapeutic interest. The small molecule G-1, an agonist directed against the membrane-bound estrogen receptor GPER, is known to attenuate the multiple sclerosis-like animal model EAE. However, its effects on CD4+ T cell populations were previously unknown. Using cultures of purified CD4+ T cells, we show that G-1 can elicit ERK-dependent expression of IL10. G-1 treated cultures secreted 3-fold more IL10, with no change in the proinflammatory cytokines IL17A, TNFα, and IFNy. Analysis of Foxp3 and RORyt expression demonstrated increased percentages of IL10+ cells in both the TH17 (RORyt+) and Foxp3+RORyt+ hybrid T cell compartments. We also show that, in mice, in vivo treatment with G-1 leads to increased IL10 secretion from splenocytes. These results demonstrate that G-1 acts directly on CD4+ T cells, and to our knowledge provide the first example of a synthetic small molecule capable of eliciting IL10 expression in TH17 or hybrid T cell populations. While G-1 treatment was not effective in a murine model of colitis, investigations of its effects in other T cell-based disease models are warranted

Untersuchung zur Bedeutung der Expression von Vimentin im invasiven Mammakarzinom

Das Vorhandensein von Vimentin in invasiven Mammakarzinomen wird meistens durch zwei Theorien erklärt: durch eine epithelial-mesenchymale Transition (EMT) oder durch eine direkte Entstehung aus myoepithelialen Zellen. Im Rahmen dieser Arbeit wurden 366 Mammabiopsien mit invasiven Tumorkomponenten auf die Expression von Vimentin und von 15 weiteren Markern untersucht. Die Expression von Vimentin korrelierte signifikant mit dem Tumorgrad sowie mit der Expression von SMA, p53, EGFR, CK5, CD10 und Mib-1. Die dargestellten Ergebnisse zeigen, dass eine Vimentin-Expression in einem invasiven Mammakarzinom nicht allein mit einer EMT oder einer myoepithelialen Histogenese erklärt werden kann. Es muss daher angenommen werden, dass noch ein weiterer Entstehungsweg dieser Vimentin-positiven Mammakarzinome existiert. Denkbar wäre hier die alternative Theorie, dass Vimentin-exprimierende Brusttumore aus Progenitorzellen mit bilinearem Differenzierungspotential entstehen könnten

Fully automated convolutional neural network-based affine algorithm improves liver registration and lesion co-localization on hepatobiliary phase T1-weighted MR images.

BackgroundLiver alignment between series/exams is challenged by dynamic morphology or variability in patient positioning or motion. Image registration can improve image interpretation and lesion co-localization. We assessed the performance of a convolutional neural network algorithm to register cross-sectional liver imaging series and compared its performance to manual image registration.MethodsThree hundred fourteen patients, including internal and external datasets, who underwent gadoxetate disodium-enhanced magnetic resonance imaging for clinical care from 2011 to 2018, were retrospectively selected. Automated registration was applied to all 2,663 within-patient series pairs derived from these datasets. Additionally, 100 within-patient series pairs from the internal dataset were independently manually registered by expert readers. Liver overlap, image correlation, and intra-observation distances for manual versus automated registrations were compared using paired t tests. Influence of patient demographics, imaging characteristics, and liver uptake function was evaluated using univariate and multivariate mixed models.ResultsCompared to the manual, automated registration produced significantly lower intra-observation distance (p < 0.001) and higher liver overlap and image correlation (p < 0.001). Intra-exam automated registration achieved 0.88 mean liver overlap and 0.44 mean image correlation for the internal dataset and 0.91 and 0.41, respectively, for the external dataset. For inter-exam registration, mean overlap was 0.81 and image correlation 0.41. Older age, female sex, greater inter-series time interval, differing uptake, and greater voxel size differences independently reduced automated registration performance (p ≤ 0.020).ConclusionA fully automated algorithm accurately registered the liver within and between examinations, yielding better liver and focal observation co-localization compared to manual registration

The Endoplasmic Reticulum Chaperone Protein GRP94 Is Required for Maintaining Hematopoietic Stem Cell Interactions with the Adult Bone Marrow Niche

Hematopoietic stem cell (HSC) homeostasis in the adult bone marrow (BM) is regulated by both intrinsic gene expression products and interactions with extrinsic factors in the HSC niche. GRP94, an endoplasmic reticulum chaperone, has been reported to be essential for the expression of specific integrins and to selectively regulate early T and B lymphopoiesis. In GRP94 deficient BM chimeras, multipotent hematopoietic progenitors persisted and even increased, however, the mechanism is not well understood. Here we employed a conditional knockout (KO) strategy to acutely eliminate GRP94 in the hematopoietic system. We observed an increase in HSCs and granulocyte-monocyte progenitors in the Grp94 KO BM, correlating with an increased number of colony forming units. Cell cycle analysis revealed that a loss of quiescence and an increase in proliferation led to an increase in Grp94 KO HSCs. This expansion of the HSC pool can be attributed to the impaired interaction of HSCs with the niche, evidenced by enhanced HSC mobilization and severely compromised homing and lodging ability of primitive hematopoietic cells. Transplanting wild-type (WT) hematopoietic cells into a GRP94 null microenvironment yielded a normal hematology profile and comparable numbers of HSCs as compared to WT control, suggesting that GRP94 in HSCs, but not niche cells, is required for maintaining HSC homeostasis. Investigating this, we further determined that there was a near complete loss of integrin α4 expression on the cell surface of Grp94 KO HSCs, which showed impaired binding with fibronectin, an extracellular matrix molecule known to play a role in mediating HSC-niche interactions. Furthermore, the Grp94 KO mice displayed altered myeloid and lymphoid differentiation. Collectively, our studies establish GRP94 as a novel cell intrinsic factor required to maintain the interaction of HSCs with their niche, and thus regulate their physiology

Regulation of basal cellular physiology by the homeostatic unfolded protein response

The extensive membrane network of the endoplasmic reticulum (ER) is physically juxtaposed to and functionally entwined with essentially all other cellular compartments. Therefore, the ER must sense diverse and constantly changing physiological inputs so it can adjust its numerous functions to maintain cellular homeostasis. A growing body of new work suggests that the unfolded protein response (UPR), traditionally charged with signaling protein misfolding stress from the ER, has been co-opted for the maintenance of basal cellular homeostasis. Thus, the UPR can be activated, and its output modulated, by signals far outside the realm of protein misfolding. These findings are revealing that the UPR causally contributes to disease not just by its role in protein folding but also through its broad influence on cellular physiology

The Incidence of Pulmonary Embolism and Associated FDG-PET Findings in IV Contrast-Enhanced PET/CT

Rationale and objectivesMost fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography with computed tomography (PET/CT) studies are performed on cancer patients. These patients are at increased risk of pulmonary embolism (PE). In this retrospective review, we determined the rate of PE, and the prevalence of associated FDG-PET findings on intravenous (IV) contrast-enhanced PET/CT.Materials and methodsWe identified all PET/CT studies performed at our institution with a reported finding of PE between January 2005 and October 2012. The medical record was reviewed for symptoms, which were identified after the diagnosis of PE, and whether the patients received treatment. The prevalence of associated FDG-PET findings was determined.ResultsA total of 65 total cases of PE (of 182,72 total PET/CT examinations) were identified of which 59 were previously unknown. This gives an incidental PE (IPE) rate of 0.32%. Of the patients where sufficient clinical information was available, 34 of 36 (94%) were treated either with therapeutic anticoagulation or inferior vena cava filter, and 30 of 36 (83%) were asymptomatic in retrospect. Of the patients with IPE, we found nine (15.2%) with associated focal pulmonary artery hypermetabolism, three (5.1%) with hypermetabolic pulmonary infarction, and one with increased isolated right ventricular FDG uptake (1.7%). One case of chronic PE demonstrated a focal hypometabolic filling defect in a pulmonary artery on PET.ConclusionsWe found IPE in 0.32% of PET/CT scans. Focal pulmonary artery hypermetabolism or hypometabolism, and hypermetabolic pulmonary artery infarction with the "rim sign" were uncommonly associated with PE. These findings could raise the possibility of IPE in non-IV contrast-enhanced PET/CT studies

The unfolded protein response in immunity and inflammation.

The unfolded protein response (UPR) is a highly conserved pathway that allows the cell to manage endoplasmic reticulum (ER) stress that is imposed by the secretory demands associated with environmental forces. In this role, the UPR has increasingly been shown to have crucial functions in immunity and inflammation. In this Review, we discuss the importance of the UPR in the development, differentiation, function and survival of immune cells in meeting the needs of an immune response. In addition, we review current insights into how the UPR is involved in complex chronic inflammatory diseases and, through its role in immune regulation, antitumour responses.This work was supported by the Netherlands Organization for Scientific Research Rubicon grant 825.13.012 (J.G.); US National Institutes of Health (NIH) grants DK044319, DK051362, DK053056 and DK088199, and the Harvard Digestive Diseases Center (HDDC) grant DK034854 (R.S.B.); National Institutes of Health grants DK042394, DK088227, DK103183 and CA128814 (R.J.K.); and European Research Council (ERC) Starting Grant 260961, ERC Consolidator Grant 648889, and the Wellcome Trust Investigator award 106260/Z/14/Z (A.K.).This is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nri.2016.6

Landeskundliche Abbildungen in Lehrbüchern für Deutsch als Fremdsprache - Die Entwicklung des Bildeinsatzes in den Jahren 2000 bis 2010

Brunsing T. Landeskundliche Abbildungen in Lehrbüchern für Deutsch als Fremdsprache - Die Entwicklung des Bildeinsatzes in den Jahren 2000 bis 2010. Informationen Deutsch als Fremdsprache (InfoDaF). 2016